KR20230058107A - Antiviral compound formulation - Google Patents

Abstract

A compound of formula I or a pharmaceutically acceptable salt thereof, wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester, O-linked selected from carbamates, S-linked phosphothioates, or N-linked phosphoramidites), and cysteine compounds, amino acids, N -acetyl amino acids, acids or salts thereof, or any combination thereof. A pharmaceutical composition comprising one pharmaceutically acceptable excipient. The pharmaceutical composition can be used for the effective treatment of viral infections in humans and other animal species caused by viruses, specifically RNA viruses, and can be administered orally or parenterally.
[Formula I]

Description

Antiviral compound formulation

The present disclosure relates to pharmaceutical compositions and methods of administration of antiviral drugs for the effective treatment of viral infections in humans and other animal species by viruses, specifically RNA viruses. Antiviral drugs are nucleoside analogs, nucleotide analogs, prodrugs of nucleoside analogs, or prodrugs of nucleotide analogs capable of inhibiting viral genome replication.

Viral infections can have detrimental effects on life. In addition to the immediate health effects of infected individuals, the contagiousness of some viral infections can also have a profound impact on the functioning of communities, businesses, services and entire economies. This is exemplified, for example, by COVID-19, a novel viral infection that emerged in 2019 and resulted in a worldwide pandemic. COVID-19 presents a risk of severe respiratory failure and death in some patients. In many cases, an acute course of symptoms occurs in elderly patients and those with underlying medical conditions such as hypertension or diabetes.

Coronaviruses are specifically enveloped RNA viruses with positive-sense, single-stranded RNA genomes that infect both animals and humans. Diseases from coronaviruses include the common cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS-CoV) caused by coronavirus 2, the pathogen that causes the disease commonly known as COVID-19. -2). The rapid emergence and spread of such viral infections results in less time to develop a vaccine. In the absence of a clinically effective and safe vaccine, widespread immunization and control of the virus becomes nearly impossible. Therefore, along with vaccine development, effective treatment of viral diseases such as COVID-19 is also required.

Antiviral compounds that mimic the structure of naturally occurring nucleosides and nucleotides constitute an important part of the drug arsenal against viral infections. Nucleosides are part of the building blocks of DNA and RNA, which are derived from the attachment of a sugar to a nucleobase of a molecule, such as adenosine from the nucleobase adenine and guanosine from guanine. Further addition of a phosphate group results in the formation of so-called nucleotides. Nucleotides containing three phosphate groups, i.e. triphosphate nucleosides, are the forms present in RNA or DNA strands. Nucleoside analogs and nucleotide analogs compete with their natural counterparts to inhibit the polymerases that help assemble the viral genome. These analogs can also be incorporated as defective components and act as chain terminators by breaking chains of hydrogen bonds between nucleotides in a growing DNA or RNA strand. Such analogues are used as drugs for many serious viral diseases including acquired immunodeficiency syndrome (AIDS), hepatitis, herpes and smallpox.

Remdesivir (also known as GS-5734), a monophosphate nucleotide prodrug, recently approved for use against COVID-19, also exhibits antiviral properties against a range of other viral infections. Remdesivir is a lipophilic adenosine monophosphate analog that is converted inside cells to the active triphosphate (GS-443902). While remdesivir has recently shown efficacy in the treatment of viral infections such as COVID-19, current pharmaceutical compositions of remdesivir have only been developed for intravenous administration. The first proof-of-concept of therapeutic activity in vivo was achieved by administering 10 mg/kg body weight once daily by intravenous (IV) injection of remdesivir against Ebola virus in non-human primates.

Currently marketed pharmaceutical compositions of remdesivir are formulated as either a lyophilized powder of remdesivir or a concentrated solution that is directly diluted with water for injection. Both formulations contain very high amounts of sulfobutylether β-cyclodextrin (SBE β CD), up to 30 to 60 times the remdesivir dose weight, as complexing and solubilizing excipients. Accordingly, up to 6 g of SBE β CD can be administered by intravenous infusion together with a 100 mg unit dose of remdesivir. This is disadvantageous because, after intravenous administration, cyclodextrin is excreted intact by renal excretion and can accumulate in the kidney at high doses. This causes vacuolation of tubular cells in the kidney, possibly leading to kidney damage. In children and patients with lower glomerular filtration rates due to impaired kidneys, high doses of SBE β CD may result in osmotic nephropathy and additional renal side effects due to higher blood levels of SBE β CD and increased osmolarity . Thus, there is a need for the development of cyclodextrin-free pharmaceutical compositions that ensure that nucleoside analogs such as remdesivir are still effectively solubilized.

Furthermore, it is believed that prior art compositions of nucleoside analogs and nucleotide analogs, including remdesivir, cannot be used by different routes of administration due to a number of factors including its limited solubility. For oral administration, prior art compositions containing remdesivir suffer from poor absorption in the stomach and intestine, instability in the intestinal medium and membranes, in the blood, and hepatic first pass metabolism (e.g., presence of many CYP and carboxylase enzymes). It is predicted to have low bioavailability as a result of accumulation and toxicity risk in the liver, and as a result of both.

It is therefore an object of the inventors to develop improved pharmaceutical compositions and methods of administration of nucleoside analogs and nucleotide analogs, such as remdesivir, with improved bioavailability. It is also an object of the present inventors to develop pharmaceutical compositions that can be used in various modes of administration including oral administration and/or administration by injection.

In a first aspect, a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical composition selected from cysteine compounds, amino acids, amino acid salts, N-acetyl amino acids, acids or salts thereof, or any combination thereof A pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient:

[Formula I]

wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester, O-linked carbamate, and S-linked phosphothioate, or N-linked phosphoramidites. The amino acid salt may be a hydrochloride salt. Such pharmaceutically acceptable excipients are widely considered safe and well tolerated. In some embodiments, the at least one pharmaceutically acceptable excipient is an acidulant or a pH adjusting agent used to reduce the pH of a solution. In some embodiments, an acid is an organic acid.

In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound. As shown in the examples, using certain cysteine compounds that exhibit improved solubilization compared to sulfobutylether beta-cyclodextrin (SBE β CD), pharmaceutical compositions comprising at least one cysteine compound are antiviral according to Formula I Indicates improved solubilization of the compound. In some embodiments, the % w/w ratio of the at least one cysteine compound to the compound of Formula I is at least 1:1, or optionally greater than 1.5:1. In some embodiments, the at least one cysteine compound comprises cysteine, glutathione (ie, cysteine containing dipeptide), cysteine hydrochloride, N-acetyl-cysteine, or combinations thereof. In some embodiments, the at least one cysteine compound comprises cysteine hydrochloride and/or N-acetyl-cysteine. In some embodiments, the at least one cysteine compound comprises cysteine hydrochloride and N-acetyl-cysteine. In some embodiments, the at least one cysteine compound can be an acidulant or a pH adjusting agent used to lower the pH of a solution.

In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one acid or salt thereof. Acids can act as acidulants. In some instances, an acid can be an organic acid. The at least one organic acid or salt thereof may be selected from lactic acid, acetic acid, citric acid, formic acid, oxalic acid, ascorbic acid, uric acid, malic acid, tartaric acid, or any combination thereof. Organic acids and their salts can in some instances improve the solubilization of antiviral compounds such as remdesivir. In some embodiments, the pharmaceutical composition comprises a combination of at least one acid or salt thereof and at least one cysteine compound. In some embodiments, an acid is an organic acid.

In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one N-acetyl amino acid. In some embodiments, the at least one N-acetyl amino acid comprises N-acetyl alanine or N-acetyl cysteine. In some embodiments, the at least one pharmaceutically acceptable excipient comprises an amino acid hydrochloride. In some embodiments, the pharmaceutical composition comprises at least one amino acid hydrochloride and at least one cysteine compound, or at least one amino acid hydrochloride and at least one N-acetyl amino acid.

The at least one pharmaceutical excipient can improve the dissolution and solubilization of the compound of Formula I in aqueous solution and improve the bioavailability compared to prior art pharmaceutical compositions. As a result, the pharmaceutical composition described herein, in contrast to the problem of poor bioavailability of antiviral compounds such as remdesivir, provides patients with an appropriate unit dose for effective treatment without increasing the risk of toxicity and side effects. can be passed on.

In some embodiments, the pharmaceutical composition is formulated so that the compound of Formula I has a solubility greater than 0.05 mg/mL when placed in an aqueous solution at pH 3 to 7, or pH 4 to 6.5, or pH 4.5 to 6.0, or pH 5 to 5.5. gets angry This can ensure that the compound of formula I can remain in solution when administered as an injectable solution within an acceptable pH range, and can also be easily absorbed from the small intestine and generally the gastrointestinal tract after oral administration.

In some embodiments, the pharmaceutical compositions described herein are free of cyclodextrins (e.g., free of sulfobutylether cyclodextrins) that can interfere with other biochemical processes in the patient's body, unlike previous remdesivir compositions. ). It is also known that in certain cases, cyclodextrins also accumulate in the kidneys, causing kidney damage.

In some embodiments, the pharmaceutical composition is a liquid formulation. Liquid formulations may be advantageous because the compounds of formula I are previously solubilized. In some instances, liquid formulations described herein may be administered directly or may be formed by dilution. In both cases, liquid formulations are advantageous because they avoid additional compounding steps and reconstitution of the powder, which can be time consuming and costly, and increase the likelihood of incorrect dosing. The risk of inadvertent exposure to the manufacturer can also be significantly reduced.

In some embodiments, the pharmaceutical composition is a solution, suspension or mixture thereof.

In some embodiments, the pH of the liquid formulation is less than 8.5, optionally between pH 1 and less than 8 of the liquid formulation. As demonstrated in the examples of this application, acidic pH and/or the presence of an acidulant can improve the solubilization of the compound of Formula I.

In some embodiments, the pharmaceutical composition includes one or more co-solvents. In some embodiments, one or more co-solvents may aid in solubilizing the compound of Formula I. In some embodiments, one or more co-solvents can reduce precipitation of the compound when the pharmaceutical composition is added to an aqueous solution. In some embodiments, the pharmaceutical composition comprises one or more co-solvents in combination with a compound of Formula I and one or more pharmaceutical excipients selected from cysteine compounds, amino acid hydrochlorides, N-acetyl amino acids, or inorganic and organic acids. In some embodiments, the one or more cosolvents include low molecular weight polyethylene glycol (PEG), propylene glycol, benzyl alcohol, ethanol, or combinations thereof.

In some embodiments, the pharmaceutical composition includes PEG. In some embodiments, PEG is present in an amount greater than 40% w/w of the pharmaceutical composition. In some embodiments, PEG has a molecular weight between 200 and 1000. In some embodiments, PEG has a molecular weight between 200 and 600. In some embodiments, PEG has a molecular weight of 300 and/or 400. In some embodiments, the pharmaceutical composition comprises a combination of PEG and benzyl alcohol. In some embodiments, the pharmaceutical composition comprises a combination of PEG and ethanol. In some embodiments, the pharmaceutical composition comprises a combination of PEG, benzyl alcohol and ethanol. In some embodiments, one or more co-solvents are free of ethanol. This can improve the stability of the pharmaceutical composition, for example the stability of a compound of Formula I such as remdesivir.

In some embodiments, the pharmaceutical composition includes one or more surfactants. In some embodiments, the one or more surfactants are polysorbates or polyoxyn castor oil, where n is 30 to 40, or block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). polymers such as poloxamers (eg poloxamer 188) or Pluronic ^® . In some embodiments, the one or more surfactants can include polysorbate 20, 40, 60, 80, polyoxyl 35 castor oil, or combinations thereof. In some embodiments, the one or more surfactants are polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 35 castor oil, cremophor, polyoxyethylene (20) sorbitan monool poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers such as poloxamers (e.g., Poloxamer 188), or a combination thereof. In some embodiments, the pharmaceutical composition comprises a polysorbate (eg, polysorbate 80) in combination with a triblock copolymer (eg, a poloxamer, such as poloxamer 188). In some embodiments, the one or more surfactants (or at least one of the one or more surfactants) has an HLB value of 10 to 20, optionally 12 to 18, or optionally 14 to 16, optionally about 15. In some embodiments, the one or more surfactants can include a polysorbate, such as polysorbate 80. In some embodiments, the pharmaceutical composition includes two surfactants. In some embodiments, the pharmaceutical composition comprises a first surfactant having an HLB value of 10 to 20, optionally 12 to 18, or 14 to 16, optionally about 15, and an HLB greater than 20, for example about 25 to 35 A second surfactant having a value of In some embodiments, the one or more surfactants will exhibit improved solubilization of the compound of Formula I and/or other excipients and/or will reduce precipitation or phase separation of any components of the formulation when the pharmaceutical composition is added to an aqueous solution. can In some embodiments, the pharmaceutical composition comprises a compound of Formula I and one or more surfactants in combination with one or more pharmaceutical excipients selected from cysteine compounds, amino acid hydrochlorides, N -acetyl amino acids or acids. In some embodiments, an acid is an organic acid. In some embodiments, the pharmaceutical composition comprises one or more surfactants in combination with one or more co-solvents, compounds of Formula I, and one or more pharmaceutical excipients selected from cysteine compounds, amino acid hydrochlorides, N -acetyl amino acids, inorganic or organic acids. do.

In some embodiments, the pharmaceutical compositions described herein are compatible with various modes of administration. Accordingly, the present disclosure provides pharmaceutical compositions having increased solubility of a compound of Formula I as compared to known pharmaceutical compositions. The present disclosure may also provide pharmaceutical compositions having increased stability of a compound of Formula I (eg, in solution) compared to a reconstituted solution comprising remdesivir used for IV administration. These pharmaceutical compositions can be administered by a variety of methods, including oral administration and parenteral administration by injection or inhalation, spray, intratracheal instillation or nasal administration. In some embodiments, the pharmaceutical composition is an oral or parenteral dosage form.

In some embodiments, the pharmaceutical composition is an oral dosage form and the method of administration is oral administration. Oral administration may be less invasive than other forms of administration. As a result, the oral dosage form can be easily self-administered by a patient without the assistance of a professional medical staff. Oral formulations can therefore be used more broadly to treat a larger number of infected individuals, including patients who cannot or do not require coming to a hospital for such treatment. It is also possible to supplement and extend patient care by switching from intravenous dosing and formulations in hospitals to such oral formulations, enabling these patients to continue treatment after discharge from the hospital, so that patients with chronic underlying diseases or who are immunocompromised. More fragile patients, such as weakened individuals, may reduce the risk and cost of acquiring other infections in the hospital. In the case of a pandemic like COVID-19, the availability of oral formulations and dosage forms, and the option to be treated at home or out of hospital, could reduce the risk of disease transmission and open hospitalization opportunities for critically ill patients. With oral administration, even if the patient is at home and the disease progress is early, treatment can be initiated at the discretion of the health care provider if the symptoms are still mild and can be managed without hospitalization.

In some embodiments, the pharmaceutical composition is an injectable solution and the method of administration is by injection. In some embodiments, the injection is an intravenous or subcutaneous injection. Compared to the intravenous pharmaceutical compositions of the prior art, the pharmaceutical compositions of the present application can solubilize the compound of Formula I more effectively than the compositions of the prior art. This may be advantageous in preparing an injectable solution with a reduced risk of side effects, and may also lead to more precise dosing.

In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutically acceptable excipients (i.e., at least one pharmaceutical excipient selected from cysteine compounds, amino acid hydrochlorides, N-acetyl amino acids, acids or salts thereof). in addition to) can be included.

The pharmaceutical excipients described herein can improve the physical and chemical stability of compounds of Formula I over previous compositions. The pharmaceutical excipients described herein may additionally protect and/or enhance the shelf life of the resulting compound of Formula I. In addition to any of the pharmaceutical excipients described herein (e.g., at least one pharmaceutical excipient selected from cysteine compounds, amino acid hydrochlorides, N-acetyl amino acids, acids or salts thereof), complexing agents, polymers, surfactants, metals salts, chelating agents, antioxidants, phospholipids and other amphoteric molecules to form liposomes and micelles, or combinations thereof) additionally protect products comprising compounds of formula I from chemical degradation and/or The intestinal and cellular absorption of the compounds of I may be improved.

In some embodiments, the pharmaceutical composition has improved storage stability compared to compositions of known antiviral compounds, such as remdesivir.

In some embodiments and examples, the metabolized active product of a compound of Formula I is Compound D:

[Compound D]

.

.

In some embodiments and examples, compounds of Formula I are:

.

.

This compound is otherwise known as remdesivir. Remdesivir has good antiviral properties against SARS-CoV-2 and other viral infections.

또는 이의 염 형태이다. 이는 렘데시비르의 자유 뉴클레오시드 변이체(GS-441524)이나, 세포 내에서 활성 삼인산염(즉, 화합물 D)으로 포스포릴화될 수 있다.In an alternative embodiment, the compound of Formula I is

or a salt form thereof. It is a free nucleoside variant of remdesivir (GS-441524), but can be phosphorylated intracellularly to an active triphosphate (i.e. Compound D).

In another embodiment, the pharmaceutical composition comprises a compound of Formula I which is a chemically modified analog or natural metabolite of remdesivir. Chemical modifications to remdesivir include 1) the use of different O-linked phosphoramidites containing modified forms of alanine metabolites; 2) the use of O-linked phosphoramidites with different stereochemistry than remdesivir, 3) analogs such as O-linked esters, O-linked carbamates, or hydroxylate salts (which are use of a cleoside (GS-441524), which in some cases may have improved solubility and/or stability compared to remdesivir); 4) the use of salt forms of the compounds of Formula I; and 5) reduced logP and/or increased logS, where 'P' represents the octanol-water partition coefficient of the compound of Formula I, which is a measure of lipophilicity, and 'S' represents the solubility compared to remdesivir. ).

treatment method

In a second aspect, a method for treating a viral infection is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the viral infection is an RNA viral infection. In some embodiments, the virus causing the viral infection is a coronavirus, respiratory syncytial virus, ebola, hepatitis, junin, lassa fever, orthomyxovirus, hepatitis virus (HV) type, disease-causing Picornavirus, Ebola, SARS, MERS, respiratory syncytial virus and other pneumococcal viruses, flu, polio measles and adult human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) retroviruses, including In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is SARS-CoV-2.

In some embodiments, the pharmaceutical composition is administered orally. In another embodiment, the pharmaceutical composition is administered by injection. In some embodiments, the pharmaceutical composition is administered by inhalation, nebulization, intratracheal instillation or nasal administration. In some embodiments, the injection is an intravenous or subcutaneous injection.

In some embodiments, the pharmaceutical composition for use in a method of treating a viral infection is a liquid formulation. In some embodiments, the amount of liquid formulation administered orally is from about 1 mL to about 6 mL of liquid formulation. In some embodiments, the amount of liquid formulation administered by intravenous infusion is from about 100 mL to about 250 mL after dilution of 1 to 40 mL of the liquid formulation containing a higher concentration of the active ingredient than the final infusion solution.

In some embodiments of the pharmaceutical composition for use in a method of treating a viral infection, the amount of compound of Formula I administered is between 20 mg and 300 mg, or between 50 mg and 250 mg, or between 100 mg and 200 mg. In some embodiments, the amount of compound of Formula I administered is greater than 20 mg, or greater than 50 mg, or greater than 75 mg, or greater than 90 mg. In some embodiments, the amount of compound of Formula I administered is less than 180 mg, or less than 160 mg, or less than 140 mg, or less than 120 mg.

Capsule(s), oral solution(s) and injectable solution(s)

In a third aspect, a capsule comprising a pharmaceutical composition as described herein is provided. In an embodiment, the capsule is a liquid-filled capsule. In some embodiments, the liquid-filled capsule has a volume of about 0.4 mL to about 0.9 mL, optionally about 0.6 mL to about 0.8 mL, optionally about 0.7 mL (i.e., wherein the volume corresponds to the amount of liquid formulation in the capsule). have

In a fourth aspect, an oral solution comprising a pharmaceutical composition as described herein is provided. Oral solutions may be in the form of medicines, syrups, elixirs, or syrups or suspensions.

In a fifth aspect, an injectable solution comprising a pharmaceutical composition as described herein is provided.

Details, examples and preferences provided in relation to any one or more of the mentioned aspects of the invention will be further described herein, and apply equally to all aspects of the invention. Any combination of implementations and preferences described herein, in all possible variations thereof, is embraced by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Figure 1: Stability of remdesivir in solution at different pHs, as determined by the percent degradation of the compound per hour at 40 °C.
Figure 2: Shows the % dissolution of the active compound in aqueous solution over time. Diamond data values correspond to exemplary pharmaceutical compositions of the present invention (hollow diamonds, broken lines - no capsules, solid diamonds, solid lines - filled into hard gelatin capsules). Circular data points with thin dashed lines correspond to comparative controls comprising acetaminophen, a powdered drug with high bioavailability, filled in hard gelatin capsules. The square data points represent the dissolution of the remdesivir drug substance as a powder filled in a hard gelatin capsule, with (hollow squares) or without any other excipients (solid squares) the solubilizing excipient, SBE β CD.
Figure 3: Mean plasma of remdesivir metabolite compound C, namely GS-441524, in male beagle dogs after a 30 min IV infusion (light line) or a single PO dose (dark line) of 20 mg/kg remdesivir. represents a profile.

Where ranges are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or range of numbers means that the number or range of numbers referred to is an approximation within experimental variability (or within statistical experimental error), such that the number or range of numbers may vary. Conventional experimental variability may result, for example, from changes and adjustments required during scale-up from laboratory experiments and manufacturing environments to larger scale GMP manufacturing conditions, as known to those familiar with the fields of pharmaceutical development and manufacturing. same. Such variations may vary between 1% and 10% of the recited number or range of numbers.

The term "prodrug" may or may not have pharmacological activity by itself, but may or may not have pharmacological activity, but may or may not have chemical activity within a subject's body after administration, due to metabolism or exposure to a physiological medium, or from biochemical processes within cells. refers to a molecule that is altered to, or otherwise produces a pharmacologically active drug after administration. A pharmacologically active drug in the context of this disclosure is a molecule capable of inhibiting, blocking or retarding the replication of a viral genome. In some embodiments, the pharmacologically active drug is a triphosphate.

The term "comprising" (and related terms, such as "comprises" or "comprises" or "having" or "including") is meant to be open-ended, and thus a pharmaceutical composition comprising the described features may be added in addition to the described features. , may contain additional components. The term "comprising" (and related terms) also includes an embodiment, e.g., "consisting of" or "consisting essentially of" a described feature, i.e., a material, composition, method, or process, etc., limited to those described features. It may include embodiments of any configuration.

Abbreviations used herein have their ordinary meanings in the chemical and biological arts unless otherwise indicated.

The term “oral dosage form” refers to final dosage forms and compositions thereof that are administered orally by ingestion. Oral formulations are intended to exclude intravenous formulations or any dosage forms and compositions that can be administered by injection or inhalation, or other routes of administration such as rectal, topical or transdermal.

The term "HLB value" is the hydrophilic-lipophilic balance of a surfactant. The HLB value is a measure of how hydrophilic or lipophilic a surfactant is: an HLB number greater than 10 is affinity for water (hydrophilic) and an HLB number less than 10 is affinity for oil (lipophilic). For nonionic surfactants, the HLB value is determined by the Griffin method, where HLB = 20 * M _h /M, where M _h is the mass of the hydrophilic component and M is the mass of the entire molecule. The HLB value for an ionic surfactant (ie, where the HLB value is greater than 20) can be determined using the Davies method.

The term "acidulant" refers to a compound that is an acidifying agent, that is, an agent that lowers the pH of a composition or formulation.

The term "effective amount" or "therapeutically effective amount" is defined as a reduction in severity of disease and/or complete remission of disease measurable by clinical, biochemical or other indicators familiar to those skilled in the art. refers to the amount of a compound of formula (I) or a metabolite thereof described herein that has adequate antiviral activity necessary to produce an acceptable therapeutic result as described herein. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and the viral disease being treated, as well as the disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the mode of administration, and the like. and can be easily determined by a person skilled in the art. The term also applies to doses that will induce a specific response in a target cell. The specific dosage will depend on the particular compound (i.e., compound) of Formula I selected, the dosing regimen that follows, whether or not it is administered in combination with other compounds, the route and timing of administration, the tissue being administered, and the body delivery system to which it is delivered.

The terms "treatment" and "treating" refer to an approach for obtaining a beneficial or desirable result, including but not limited to therapeutic benefit and/or prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, even though the patient may still suffer from the underlying disorder. For prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient who may not yet have been diagnosed with the disease, but who reports one or more physiological symptoms of the disease.

The term "therapeutic effect" as used herein encompasses therapeutic benefit and/or prophylactic benefit as described above. A prophylactic effect is to delay or eliminate the appearance of a disease or condition, delay or eliminate the onset of symptoms of a disease or condition, mitigate, halt, or reverse the progress of a disease or condition, or any of these contains a combination

The term “subject” or “patient” refers to an animal, such as a mammal, eg a human. The methods described herein may be useful in both human therapeutics and veterinary applications. In some embodiments the patient is a mammal, and in preferred embodiments the patient is a human. For veterinary purposes, the terms "subject" and "patient" include livestock, including cattle, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks and geese.

The term "alkyl" refers to any substituted or unsubstituted alkane that lacks one hydrogen. In some embodiments, C ₁ -C ₆ alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, s- pentyl, t-pentyl, neopentyl, 3-pentyl, sec-isopentyl or 2-methylbutyl. In some instances, C ₁ -C ₆ alkyl is considered to include C ₁ -C ₆ haloalkyl, eg where alkyl is at least one halo-substituent selected from fluoro, chloro, bromo, or iodo includes

The term "allyl" refers to any substituted or unsubstituted alkene lacking one hydrogen. In some embodiments, C ₂ -C ₆ alkenyl can include ethylene, propylene, butylene or pentylene. In some instances, C ₂ -C ₆ allyl is considered to include C ₂ -C ₆ haloallyl, eg where allyl carries at least one halo-substituent selected from fluoro, chloro, bromo or iodo. include

The term "alkynyl" refers to any substituted or unsubstituted alkyne lacking one hydrogen. In some embodiments, C ₂ -C ₆ alkynyl can include acetyline, propyline or butyline. In some instances, C ₂ -C ₆ alkynyl is meant to include C ₂ -C ₆ halo alkynyl, for example where alkynyl is at least one halo selected from fluoro, chloro, bromo or iodo -Includes substituents.

The term “phenyl” may refer to any unsubstituted or substituted phenyl. Substituted phenyl is fluoro, chloro, bromo, iodo, methoxy, ethoxy, nitrile, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, C ₂ -C ₆ alkynyl, may be substituted with one or more substituents selected from C ₁ -C ₆ alkoxy.

The term “biphenyl” includes unsubstituted biphenyls and fluoro, chloro, bromo, iodo, methoxy, ethoxy, nitrile, amino, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, and biphenyl groups substituted with one or more of C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy.

The term “alkoxy” refers to a group having the formula O-alkyl, wherein the alkyl group is as defined above.

The term “amino” refers to any nitrogen radical having the formula NX ₂ , where X is either H or alkyl, where alkyl is as defined above.

The term “heteroaryl” refers to an aromatic group containing at least one of O, N or S. In some embodiments, heteroaryl is pyridine, bipyridine, furan, indole, pyrrole, thiazole, thiophene, imidazole, oxazole, thiazole, or furazan. “Heteroaryl” means unsubstituted heteroaryl and fluoro, chloro, bromo, iodo, methoxy, ethoxy, nitrile, amino, nitro, cyano, azido, hydroxyl, C ₁ -C ₆ alkyl , alkoxy, C ₂ -C ₆ allyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy.

The term "peptide" refers to a portion of a molecule comprising at least two amino acids linked via amide bonds.

The term "O-linked ester" refers to an ester attached through an O atom.

The term “phosphoamidite” is used to describe amide phosphonic acids commonly used in the synthesis of differentially protected phosphate esters as prodrugs. Additionally, it may be useful in the synthesis of phosphate monoesters by hydrolysis of the phosphoramide linkages.

The term “O-linked phosphoramidite” refers to any phosphoramidite attached through an O atom (eg, a phosphate salt linked to N).

The term “S-linked phosphothioate” refers to any phosphothioate attached through an S atom (eg, a phosphate salt linked to S).

The term “N-linked phosphoramidite” refers to any phosphoramidite attached through an N atom (eg, a phosphate salt linked to N).

The term “O-linked phosphoester” refers to any phosphoester attached through an O atom.

The term “O-linked carbamate” refers to any carbamate attached through an O atom.

The term "logP" refers to the logarithm of the partition coefficient "P", which is defined as the ratio of the concentration of the non-ionized solute between octanol and water. In some examples, logP may be determined by chemistry software, for example by ALOGPS 2.1.

Alternatively, the term "logD" can be used to describe the LogP of an ionized moiety in water at a given pH, where "D" is defined as the distribution coefficient, and the ionized moiety between octanol and water at that pH. It is expressed as a ratio of solute concentrations.

The term “logS” refers to the water solubility of a drug and is defined as the general solubility corresponding to the 10-scale logarithm of the solubility of a molecule measured in moles/L under standard conditions. In some examples, logS can be determined by chemistry software, eg ALOGPS 2.1.

The term "bioavailability" generally describes the extent to which a given dose of a drug or its metabolite enters the systemic circulation and thereby exerts a pharmacological effect. Bioavailability also quantifies the AUC (where "AUC" refers to the area under the plasma-concentration and time curve that describes the change in drug concentration in plasma as concentration over time), which indicates that the total dose is available for systemic circulation. It can be measured by expressing it as a fraction of the AUC that would have resulted if For purposes of quantification of bioavailability, the AUC from all other routes of administration is calculated from the intravenous route of administration under the assumption that the drug is 100% bioavailable after intravenous administration and that the AUC from intravenous administration represents the maximum value for a given dose. can be divided by the AUC obtained. Plasma concentrations for estimation of AUC can be determined by a variety of analytical methods including liquid chromatography coupled mass spectrometry (LC/MS), or gas chromatography coupled mass spectrometry (GC/MS) radioisotope labeling, and the like. . Bioavailability can be expressed as the fraction, or more commonly, the percentage of therapeutically active drug that reaches the systemic circulation, compared to that via intravenous administration. As an example, for oral administration, (AUC _oral /AUC _intravenous ) is determined by Х100.

The term C _max is the maximum blood concentration achieved after drug administration.

Any method of treatment of a disease described herein, eg, a method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition described herein, is referred to as "a medicament for use in the treatment of a disease". may be referred to or expressed interchangeably. That is, when the disease is a viral infection of a particular type, the treatment method may be referred to interchangeably as "a pharmaceutical composition for use in the treatment of a viral infection".

Any structure or formula disclosed herein that is described in ionized form may also include non-ionized modifications.

pharmaceutical composition

pharmaceutical excipients

The pharmaceutical composition may include at least one pharmaceutically acceptable excipient selected from cysteine compounds, amino acid hydrochlorides, N -acetyl amino acids, acids or salts thereof, or any combination thereof. In some embodiments, said at least one pharmaceutical excipient is an acidulant.

cysteine compound

In some embodiments, at least one pharmaceutically acceptable excipient is a cysteine compound. Cysteine compounds described herein include cysteine, cysteine acid salts (eg, cysteine hydrochloride, or cysteine dihydrochloride), N-substituted cysteines (eg, N-acetyl cysteine), cysteine esters, cysteine dimers. (eg, cystine) and cysteine-containing peptides. The cysteine can be D or L cysteine or a combination thereof.

In some embodiments, the at least one cysteine compound is present in 0.5 to 50% w/w of the pharmaceutical composition, or at least 1 to 35% w/w, or at least 6 to 30% w/w of the pharmaceutical composition, or at least 6% w/w of the pharmaceutical composition. It is present in an amount of 10 to 25% w/w. In some embodiments, the at least one cysteine compound is present in an amount greater than 5% w/w of the pharmaceutical composition, or greater than 7.5% w/w, or greater than 10% w/w, or greater than 12% w/w of the pharmaceutical composition. exist. In some embodiments, the at least one cysteine compound is present in an amount less than 30% w/w of the pharmaceutical composition, or less than 25% w/w of the pharmaceutical composition.

In some embodiments, the at least one cysteine compound is selected from cysteine, cysteine hydrochloride, N-acetyl cysteine, or glutathione. In some embodiments, the at least one cysteine compound is cysteine hydrochloride and/or N-acetyl cysteine. In some embodiments, the at least one cysteine compound is a combination of cysteine hydrochloride and N-acetyl cysteine.

In some embodiments, cysteine hydrochloride is present in an amount from 0.5 to 15% w/w of the pharmaceutical composition and/or N-acetyl cysteine is present in an amount from 3 to 15% w/w of the pharmaceutical composition. In some embodiments, cysteine hydrochloride is present in an amount of 1-13% w/w of the pharmaceutical composition and/or N-acetyl cysteine is present in an amount of 5-13% w/w of the pharmaceutical composition. In some embodiments, the % w/w ratio of cysteine hydrochloride to N-acetyl chloride in the pharmaceutical composition is from 1:1 to about 1:4, or from about 1.75:1 to about 1:1.25. In some embodiments, the amount of cysteine hydrochloride is present in an amount of less than 5%, or less than 4%, or less than 3%, or less than 2.5%, or less than 2% by weight of the pharmaceutical composition. In some instances, pharmaceutical compositions comprising lower amounts of cysteine hydrochloride (i.e., up to 3% w/w) may improve the stability of a compound of Formula I, e.g., remdesivir and/or pharmaceutical formulations. .

In some embodiments, the % w/w ratio of at least one cysteine compound to the compound of Formula I in the pharmaceutical composition is at least 1:1, or alternatively greater than 1.25:1, or alternatively greater than 1.5:1, or alternatively greater than 1.75 :1, or optionally 2.1 or optionally 2.25:1, or the % w/w ratio of the at least one cysteine compound to the compound of Formula I in the pharmaceutical composition is optionally greater than 2.5:1. In some embodiments, the % w/w of the at least one cysteine compound to the compound of Formula I in the pharmaceutical composition is less than 5:1, or less than 4:1. In some embodiments, the % w/w ratio of the at least one cysteine compound to the compound of Formula I in the pharmaceutical composition is from 1:1 to 5:1.

acid or salt thereof

In some embodiments, the at least one pharmaceutically acceptable excipient is an acid or salt thereof. In some embodiments, the acid is an organic acid selected from lactic acid, adipic acid, acetic acid, citric acid, formic acid, succinic acid, oxalic acid, ascorbic acid, uric acid, malic acid, tartaric acid, or any combination thereof. Suitable salts may include, but are not limited to, sodium, potassium, calcium, magnesium and ammonium. In some embodiments, the at least one acid is present in 1 to 35% w/w of the pharmaceutical composition, or at least 2 to 30% w/w, or at least 10 to 25% w/w, or at least 3 to 20% w/w of the pharmaceutical composition. /w, or at least 4 to 15% w/w. In some embodiments, the at least one acid is present in greater than 1% w/w of the pharmaceutical composition, or greater than 2% w/w, or greater than 3% w/w, or greater than 4% w/w, or 5% w of the pharmaceutical composition. It is present in an amount greater than /w. In some embodiments, the at least one acid is less than 30% w/w of the pharmaceutical composition, or less than 25% w/w, or less than 20% w/w, or less than 15% w/w, or 10% w/w of the pharmaceutical composition. It is present in an amount less than /w. In some embodiments, the at least one pharmaceutically acceptable excipient may include at least one cysteine compound and an acid or salt thereof.

In some embodiments, the % w/w ratio of the at least one acid or salt thereof to the compound of Formula I in the pharmaceutical composition is at least 1:1, or optionally greater than 1.25:1, or optionally greater than 1.5:1, or optionally greater than 1.5:1. to greater than 1.75:1, or optionally greater than 2.1, or optionally greater than 2.25:1, or the % w/w ratio of at least one acid or salt thereof to the compound of Formula I in the pharmaceutical composition is optionally greater than 2.5:1. . In some embodiments, the % w/w ratio of the at least one acid or salt thereof to the compound of Formula I in the pharmaceutical composition is less than 5:1, or less than 4:1. In some embodiments, the % w/w ratio of the at least one acid or salt thereof to the compound of Formula I in the pharmaceutical composition is from 1:1 to 5:1.

N-Acetyl Amino Acid

In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one N -acetyl amino acid. In some embodiments, the N -acetyl amino acid is any suitable amino acid. Amino acids can be natural amino acids or non-natural amino acids. In some embodiments, an amino acid can be a D or L amino acid or a combination thereof. In some embodiments, the amino acid is alanine, valine, histidine, methionine, lysine, phenylalanine, threonine, tryptophan, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, proline, serine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan, or It may be a combination of these. In some embodiments, the N -acetyl amino acid is N -acetyl cysteine or N -acetyl alanine. In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound and at least one N -acetyl amino acid. In some embodiments, at least one cysteine compound and at least one N -acetyl amino acid can be the same compound (eg, N -acetyl cysteine). In another embodiment, the at least one cysteine compound and the at least one N -acetyl amino acid are different compounds (eg, N -acetyl cysteine in combination with cysteine hydrochloride, or N -acetyl alanine in combination with cysteine hydrochloride). can In some embodiments, the at least one N -acetyl amino acid is in an amount from 0.5 to 15% w/w of the pharmaceutical composition, or from 3 to 13% w/w of the pharmaceutical composition, or from 5 to 10% w/w of the pharmaceutical composition. exist. In some embodiments, the N -acetyl amino acid is present in greater than 3% w/w, or greater than 4% w/w, or greater than 5% w/w, or greater than 7.5% w/w, or greater than 10% w/w of the pharmaceutical composition. present in excess amounts. In some embodiments, at least one pharmaceutical composition contains N -acetyl amino acids in less than 15% w/w, or less than 12.5% w/w, or less than 10% w/w, or less than 7.5% w/w of the pharmaceutical composition. include in quantity N -acetyl amino acid can be used as an acidulant.

amino acid hydrochloride

In some embodiments, the at least one pharmaceutically acceptable excipient is an amino acid hydrochloride (ie, an amino acid hydrochloride salt). Amino acids may be natural or unnatural amino acids. Amino acids can be D or L amino acids or combinations thereof. In some embodiments, the amino acid hydrochloride is selected from cysteine hydrochloride, glycine hydrochloride or glutamic acid hydrochloride. In some embodiments, the amino acid hydrochloride is cysteine hydrochloride.

In some embodiments, the amino acid hydrochloride is present in an amount of 0.5-15% w/w in the pharmaceutical composition. In some embodiments, the amino acid hydrochloride is present in greater than 1% w/w, or greater than 2% w/w, or greater than 3% w/w, or greater than 4% w/w, or greater than 5% w/w of the pharmaceutical composition. , or greater than 7.5%, or greater than 10% w/w. In some embodiments, the at least one pharmaceutical composition is present in an amount of less than 15% w/w, or less than 12.5% w/w, or less than 10% w/w, or less than 7.5% w/w of the pharmaceutical composition. Contains amino acid hydrochloride. Amino acid hydrochloride can be used as an acidulant.

In some embodiments, the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound and at least one amino acid hydrochloride. In some embodiments, the at least one cysteine compound and the at least one amino acid hydrochloride can be the same compound (eg, cysteine hydrochloride). In other embodiments, the at least one cysteine compound and the at least one amino acid may be different compounds (eg, glycine hydrochloride and N-acetyl cysteine).

Absence of cyclodextrins

In some embodiments, the pharmaceutical composition is free of cyclodextrins. In some embodiments, the pharmaceutical composition is free of alpha, beta, and/or gamma cyclodextrins. In some embodiments, the pharmaceutical composition is free of any derivatized and/or modified cyclodextrins, such as hydroxylpropyl β -cyclodextrin and sulfobutylether β -cyclodextrin.

Liquid formulations and co-solvents

In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the liquid formulation has less than 8.5, optionally less than 7.9, or optionally less than 7.8, or optionally less than 7.7, or optionally less than 7.6, or optionally less than 6.5, or optionally less than 6.0, or optionally less than 6.0. It has a pH less than 5.5. In some embodiments, the liquid formulation has greater than 1, optionally greater than 1.2, or optionally greater than 1.4, or optionally greater than 1.6, or optionally greater than 1.8, or alternatively greater than 2.0, or alternatively greater than 2.5, or alternatively 3.0 greater than, or optionally greater than 3.5, or optionally greater than 4.0. In some embodiments, the pH is optionally in the range of 1 to less than 8.

In some embodiments, the pharmaceutical composition includes one or more co-solvents. Co-solvents may be termed solubilizers. In some embodiments, the pharmaceutical composition includes 1, 2, 3, or 4 or more co-solvents. Co-solvents include polyethylene glycol (PEG) (eg PEG 400, PEG 300, PEG 600), glycerol, DMSO, ethanol, propylene glycol, polypropylene glycol, N-methylpyrrolidone, benzyl alcohol, cetostearyl alcohol, benzylbenzoate, corn syrup, acacia syrup, glucose syrup, acetyltributyl citrate, lactic acid, acetic acid, ethyl acetate, benzoic acid, polyoxyl 35 castor oil, polysorbates 20, 40, and 80; water, peppermint oil, or combinations thereof. In some embodiments, the one or more co-solvents are or include polar solvents. In some embodiments, a polar solvent can be an aprotic solvent or a protic solvent. In some embodiments, one or more co-solvents may be free of oil. In some embodiments, the co-solvent is polyethylene glycol (PEG) (eg, PEG 300, PEG 400), N-methyl pyrrolidone, propylene glycol, water benzyl alcohol, ethanol, povidone, peppermint oil, or polyvinyl caprolactam. -polyvinyl acetate-polyethylene glycol graft copolymers, or combinations thereof. In some embodiments, the one or more solvents include polymeric solvents.

In some embodiments, the pharmaceutical composition comprises polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) or high molecular weight polyethylene glycol (MW > 600), or poly(ethylene oxide) (PEO) and poly( propylene oxide) (PPO), such as one or more solubility enhancing solid polymers such as poloxamers.

In some instances, the pharmaceutical composition comprises, by weight, at least 0.1% by weight of the total pharmaceutical composition of the co-solvent, or at least 0.5%, or at least 1%, or at least 5%, or at least 10%, or at least 20% by weight %, or at least 30% by weight, or at least 40% by weight of cosolvent, or at least 50% cosolvent by weight of the total pharmaceutical composition, or at least 60% cosolvent by weight of the total pharmaceutical composition, or by weight of the total pharmaceutical composition at least 50% co-solvent in the pharmaceutical composition, or at least 60% co-solvent in the total pharmaceutical composition by weight. In some embodiments, the pharmaceutical composition comprises less than 80%, or less than 75%, or less than 70%, or less than 65% cosolvent by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 50 to 86% w/w of one or more cosolvents, 55 to 86% w/w of one or more cosolvents, or 62 to 86% w/w of one or more cosolvents. .

In some embodiments, the one or more solvents include polymeric solvents. In some embodiments, the polymeric solvent has a molecular weight greater than 200, or greater than 225, or greater than 250, or greater than 275 molecular weight. In some embodiments, the one or more co-solvents comprises PEG, optionally wherein the PEG is present in greater than 40% w/w of the pharmaceutical composition, or greater than 50% w/w of the pharmaceutical composition, greater than 50% w/w of the pharmaceutical composition. exist in quantity. PEG is present in an amount greater than 60% w/w of the formulation. In some embodiments, the one or more cosolvents include PEG in an amount of 40 to 90% w/w of the pharmaceutical composition. In some embodiments, PEG has a molecular weight between 200 and 600.

In some embodiments, the one or more cosolvents include PEG 300 and/or PEG 400. The number following PEG indicates the average molecular weight of the polymer.

In some embodiments, the one or more cosolvents include PEG 300 and PEG 400.

In some embodiments, the pharmaceutical composition comprises 10-30% w/w PEG 300 and 35-65% w/w PEG 400. In some embodiments, the ratio of PEG 400:PEG 300 is greater than 1:1, or greater than 1.5:1, or greater than 2:1.

In some embodiments, the one or more cosolvents are selected from PEG, benzyl alcohol, ethanol, or combinations thereof.

In some embodiments, the one or more solvents include one or more alcohol compounds, eg C2-C7 alcohol compounds. In some embodiments, the one or more alcohol compounds may be selected from ethanol, benzyl alcohol, glycerol, tert-butyl alcohol (or tert-butyl alcohol), or polyethylene glycol or propylene glycol.

In some embodiments, the one or more co-solvents include one or more PEG compounds (eg, PEG 300 and PEG 400) combined with one or more alcohol compounds. In some embodiments, the one or more alcohol compounds include benzyl alcohol and/or ethanol. In some embodiments, the one or more co-solvent comprises PEG in an amount of 40 to 90% w/w of the pharmaceutical composition and one or more alcohol compounds in an amount of 2 to 12% w/w of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 49-90% w/w PEG, 2-8% w/w ethanol and/or 2-8% w/w benzyl alcohol. In some embodiments, the pharmaceutical composition comprises 49-90% w/w PEG, less than 4.5% w/w ethanol and/or 2-8% w/w benzyl alcohol. In some embodiments, the pharmaceutical composition comprises 49-90% w/w PEG, and 2-8% w/w benzyl alcohol. In some embodiments, the pharmaceutical composition may comprise less than 4.5% w/w, or less than 3% w/w ethanol, or less than 2% w/w ethanol, or less than 1% w/w ethanol, or or without ethanol.

In some embodiments, the concentration of the compound of Formula I in the pharmaceutical composition (i.e., wherein the pharmaceutical composition is present as a liquid formulation) is between 30 mg/mL and 100 mg/mL, or between 40 mg/mL and 80 mg/mL, or 50 mg/mL to 75 mg/mL.

Surfactants

In some embodiments, the pharmaceutical composition includes a surfactant. In some embodiments, the pharmaceutical composition includes 1, 2, 3, or 4 or more surfactants. In some instances, the pharmaceutical composition comprises at least 0.1% by weight of the surfactant(s), or at least 0.5% by weight, or at least 1% by weight, or at least 5% by weight, or at least 10% by weight, based on the weight of the total pharmaceutical composition, or at least 20% by weight of surfactant(s). In some embodiments, the pharmaceutical composition comprises less than 20% by weight of the surfactant(s), by weight of the total pharmaceutical composition, or less than 10% by weight, or less than 8.% by weight, or 7% by weight of the total pharmaceutical composition. % of surfactant(s). In some embodiments, the pharmaceutical composition contains 1 to 20% w/w surfactant, or 2 to 15% w/w surfactant, or 3 to 10% w/w surfactant, or 4 to 8% w/w surfactant. w surfactant, or 5 to 7% w/w surfactant, or about 6% w/w surfactant.

In some embodiments, the one or more surfactant(s) is polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 35 castor oil, cremophor, polyoxyethylene (20) sorb Bitane monooleate, polyethylene glycol sorbitan monooleate, polyoxyethylenesorbitan monooleate, or block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), such as poloxamers, or selected from combinations thereof.

In some embodiments, one or more surfactant(s) is a nonionic surfactant. In some embodiments, the one or more surfactant(s) has a weight average molecular weight of less than 5000, or less than 3000, or less than 1500. In some embodiments, the one or more surfactant(s) has a weight average molecular weight between 1000 and 1500. In some embodiments, the one or more surfactant(s) is selected from polysorbate 80 and poloxamer. In some embodiments, the one or more surfactants are polysorbates, such as polysorbate 20 (polyoxyethylene(20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene(20) sorbitan monopalmi tate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or comprising these. In one embodiment, the polysorbate is polysorbate 80. Polysorbate 80 is otherwise known and marketed as Tween 80. In some embodiments, the one or more surfactant is or comprises a poloxamer, such as poloxamer 188. In some embodiments, a pharmaceutical composition may include two surfactants. In some instances, one surfactant may be used to aid solubility of the compound of Formula I and another surfactant may be used to stabilize the compound of Formula I. In some embodiments, the pharmaceutical composition may include a polysorbate (eg, polysorbate 80) in combination with a triblock copolymer (eg, a poloxamer such as poloxamer 188).

In some embodiments, the HLB value of the one or more surfactants (ie, at least one of the one or more surfactants) is between 10 and 20, alternatively between 12 and 18, or alternatively between 14 and 17, or alternatively between 14.5 and 15.5. In some embodiments, the HLB value of one or more surfactants is greater than 10, or greater than 12, or greater than 14. In some embodiments, the HLB value of the one or more surfactants is less than 20, or less than 18, or less than 17, or less than 16 (eg, polysorbate 80).

In some instances, the pharmaceutical composition comprises at least 0.1% by weight of the polysorbate(s) (polysorbate 80), or at least 0.5% by weight, or at least 1% by weight, or at least 5% by weight of the total pharmaceutical composition. %, or at least 10%, or at least 20% polysorbate(s) (eg, polysorbate 80). In some embodiments, the pharmaceutical composition comprises less than 20% by weight of the polysorbate(s) (eg, polysorbate 80), by weight of the total pharmaceutical composition, or less than 10% by weight of the total pharmaceutical composition; or less than 8%, or less than 7% by weight polysorbate(s). In some embodiments, the pharmaceutical composition comprises 1 to 20% w/w polysorbate, or 2 to 15% w/w polysorbate, or 3 to 10% w/w polysorbate, by weight of the pharmaceutical composition. Sorbate, or 4-8% w/w polysorbate, or 5-7% w/w polysorbate, or about 6 w/w% polysorbate (e.g., polysorbate 80) includes In some instances, the pharmaceutical composition comprises at least 0.1% by weight of the poloxamer(s) (poloxamer 188), or at least 0.5% by weight, or at least 1% by weight, or at least 5% by weight of the total pharmaceutical composition. poloxamer(s) of (eg, poloxamer 188). In some embodiments, the pharmaceutical composition comprises less than 20% by weight of the poloxamer(s) by weight of the total pharmaceutical composition, or less than 10% by weight, or less than 8.% by weight, or 7% by weight of the total pharmaceutical composition. less than, or less than 5%, or less than 4%, or less than 3%, or less than 2.5%, or less than 2% of the poloxamer(s). In some embodiments, the pharmaceutical composition comprises about 0.25% to about 5% poloxamer by weight of the total pharmaceutical composition, or about 0.5% to about 4% poloxamer by weight of the total pharmaceutical composition, or 1% to about 3% by weight of a poloxamer (eg, Poloxamer 188). In some embodiments, these recited amounts of polysorbate and poloxamer can be readily combined.

compound of formula I

The pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof:

[Formula I]

wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester or O-linked carbamate, S-linked phosphothioate, or N- It is selected from linked phosphoramidites.

In some embodiments, a compound of Formula I is a prodrug.

In some embodiments, X is an O-linked phosphoramidite.

이며,In some embodiments, X is

is,

wherein R ₂ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglu Min, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H or C ₁ -C ₆ alkyl;

R ₄ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl.

In some instances, R ₃ can be selected from H, methyl, ethyl, isopropyl, isobutyl, or sec-butyl. In some instances, R ₃ is methyl.

In some embodiments, R ₂ is phenyl;

R ₃ is H or C ₁ -C ₆ alkyl, for example methyl;

R ₄ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl, and in some instances C ₁ -C ₆ alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, neopentyl, 3- pentyl, sec-isopentyl or 2-methylbutyl.

In some embodiments, R ₂ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethaine. Min, meglumine, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H or C ₁ -C ₆ alkyl, for example methyl, and

R ₄ is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, neopentyl; 3-pentyl, sec-isopentyl or 2-methylbutyl, such as 3-pentyl.

또는

이다.In some embodiments, a chiral center (*) has R or S stereochemistry. That is, X =

or

am.

In some instances, X has R stereochemistry. In these examples, the stereochemistry is different from that of remdesivir, which in some instances leads to improved bioavailability.

이며,In some embodiments, X =

is,

wherein R ₂ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglu Min, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, phenyl;

R ₄ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl,

이며,In some embodiments, X =

is,

wherein R ₂ is H, Li, Na, K, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, phenyl;

R ₄ is H, Na, Li, K, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl.

In all of the above examples, R ₂ , R ₃ and R ₄ are selected such that the compound of Formula I has a logP of less than 2, or less than 1.8, or less than 1.6, thereby lowering logP and lower lipophilicity than remdesivir. have a castle In some instances, compounds of Formula I that have a lower lipophilicity than remdesivir have been found to have higher solubility than remdesivir. In some instances, R ₂ , R ₃ and R ₄ are selected such that logS is greater than -3, or -2.5, or -2, or -1.5. For example, R ₂ can be selected from H, methyl, ethyl, or heteroaryl. In some instances, R ₃ can be H. In some instances, R ₄ can be selected from H, methyl, ethyl, or heteroaryl.

또는

이며,In some embodiments, X =

or

is,

Where W is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglu min, procaine, trimethylamine, zinc, and combinations thereof.

In some embodiments, O-linked phosphoramidites are known for remdesivir, eg, described in J. Med. Chem . 2017, 60, 5, 1648-166, the contents of which are incorporated by reference), wherein the R ₂ , R ₃ and R ₄ groups of the constituents are appropriately altered.

In some embodiments, the O-linked phosphoramidite has the following structure (ie, remdesivir, compound A, otherwise known as GS 5734). In some instances, the compound of Formula I is remdesivir.

[Compound A]

.

.

In some embodiments, the O-linked phosphoramidite has the following structure (Compound B), otherwise known as GS-6620.

[Compound B]

In some embodiments, X is an O-linked phosphoester or O-linked phosphoramidite having the structure (Formula II):

[Formula II]

wherein Y is O or NH, wherein R ₅ and R ₆ are each independently from C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl; can be chosen

In some embodiments, X is a hydroxyl group and the compound of formula I has the structure as represented by compound C. Compound C is described in J.Med. Chem . 2017, 60, 5, 1648-166, the contents of which are incorporated by reference. This compound is otherwise known as GS-441524.

[Compound C]

In some embodiments of a compound of Formula I, X is a hydroxylated salt. In some embodiments, the salt is lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, methyl glumine, procaine, trimethylamine, zinc, and combinations thereof. In some embodiments X is a metal salt hydroxylate, for example wherein the metal salt is Li, Na, Ca, Mg, Zn, or K.

In some embodiments, X is an O-linked ester. In some embodiments wherein X is an O-linked ester, X is an O-linked amino acid or an O-linked peptide. An O-linked peptide may contain any number of amino acids, for example between 2 and 10 amino acids. In some embodiments, an O-linked peptide is a dipeptide (ie, 2 amino acids), a tripeptide (ie, 3 amino acids), or a tetrapeptide (ie, 4 amino acids). In some embodiments, the O-linked peptide or O-linked amino acid is formed from any suitable natural or non-natural amino acid. In some embodiments, an amino acid is an L-amino acid, a D-amino acid, or a combination thereof. In some embodiments, the amino acid is alanine, valine, histidine, methionine, lysine, phenylalanine, threonine, tryptophan, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, proline, serine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan, or selected from combinations thereof. In some embodiments, the amino acid is selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan, or combinations thereof. In some embodiments, the amino acid is selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan, or combinations thereof.

In some embodiments, X is an O-linked ester and the compound has Formula III:

[Formula III]

wherein R ₇ can be selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, or C 2 -C ₆ alkenyl, phenyl, biphenyl, heteroaryl. Compounds of formula I comprising X as an O-linked ester can be formed by selective esterification of compounds of formula I wherein X is a hydroxyl group. In some instances, a compound of Formula I wherein X is a hydroxyl group is a suitable acid chloride (eg, R ₇ -C(=0)-Cl) or an acid anhydride (R ₇ -OC(=0)-OC(C= O)-R ₇ ), or using any other suitable esterification method known in the art.

In some embodiments, X is an O-linked carbamate. In some embodiments, X is an O-linked carbamate and the compound has Formula IV:

[Formula IV]

wherein R ₈ may be selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl or C ₂ -C ₆ alkenyl, phenyl, biphenyl or heteroaryl.

In some embodiments, X is an S-linked phosphothioate. In some embodiments, X is an S-linked phosphothioate and the compound has formula V:

[Formula V]

wherein R ₉ and R ₁₀ may each be selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl or heteroaryl.

일 수 있으며,In some embodiments, X is an S-linked phosphothioate and X is

can be,

wherein R ₁₁ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglu Min, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₁₂ is H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, phenyl;

R ₁₃ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl.

In some embodiments, X is an N-linked phosphoramidite. In some embodiments, X is an N-linked phosphoramidite and the compound has Formula VI:

[Formula VI]

wherein R ₁₄ and R ₁₅ may each be selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₆ allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl.

일 수 있으며,In some embodiments, X is an N-linked phosphoramidite and X is

can be,

Here, R ₁₆ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, methyl glumine, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₁₇ is H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, phenyl;

R ₁₈ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, or C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl.

In some embodiments, for example X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester or O-linked carbamate, The metabolized active product of the compound is compound D.

[Compound D]

That is, compounds of formula I can be metabolized to compounds D in human or animal cells. Compound D is otherwise known as GS-443902. Compounds of Compound D may be in ionized or non-ionized form.

In some embodiments, the compound can be metabolized to monophosphate Compound E in human or animal cells. Compound E can be phosphorylated twice in human or animal cells by one or more kinase enzymes. Compounds of formula I, wherein X is an O-linked phosphoramidite and an O-linked phosphoester, can be metabolized first to compound E by hydrolysis, thereby potentially being rate-limiting in human or animal cells. It does not require a monophosphorylation reaction.

[Compound E]

이고,In some embodiments, for example X is

ego,

A compound of formula I is metabolized to a compound of formula VII:

[Formula VII]

.

.

In some embodiments, for example X is OH, hydroxylate salt, O-linked phosphoester or O-linked phosphoramidite, O-linked ester, O-linked carbamate, the compound of Formula I is free It can be metabolized to hydroxyl (eg Compound C). In some embodiments, compounds of Formula I are metabolized to free hydroxyls by esterase or amidase enzymes. In some embodiments, compounds of Formula I are metabolized to free hydroxyls by hydrolysis. A free hydroxyl can be phosphorylated three times by one or more kinase enzymes in human or animal cells, first to a monophosphate (ie, compound E), which is further phosphorylated to a triphosphate (ie, compound D).

In some embodiments, X is an S-linked phosphothioate and the metabolized active product of the compound of Formula I is Compound F:

[Compound F]

.

.

In some embodiments wherein X is an N-linked phosphoramidite, the metabolized active product of the compound of formula I is compound G:

[Compound G]

.

.

In some embodiments, compounds of Formula I have any suitable logP. In some embodiments, a compound of Formula I has a logP of less than 2.2. Remdesivir has a logP of 2.1. In an alternative embodiment, the compound of Formula I has a log P of less than 2, or less than 1.8, or less than 1.6, or less than 1.4, or less than 1.2, or less than 1. In some embodiments, a compound of Formula I has a logP greater than -1, or greater than -0.5, or greater than zero. In some embodiments, a compound of Formula I has a logP of -1 to 2.2, or -1 to 2, or 0 to 2.2, or 0 to 2.

In some embodiments, the pharmaceutical composition comprises at most 15% w/w of a compound of Formula I, or at most 14%, or at most 13%, or at most 12%, or at most 11%, or at most 10%, or at most 9% w /w, or up to 8% w/w, or up to 7% w/w of a compound of Formula I. In some embodiments, the pharmaceutical composition comprises 0.05 to 20% w/w of a compound of Formula I, or 1 to 18% w/w, or 2 to 16% w/w, or 3 to 14% w/w, or 4 to 12% w/w, or 5 to 10% w/w, or 6 to 8% w/w of a compound of Formula I.

In an example of a pharmaceutical composition, the compound of Formula I is remdesivir.

Examples of Pharmaceutical Compositions

In some embodiments, the pharmaceutical composition

0.05 to 20% w/w of a compound of formula I, optionally 4 to 10% w/w, or optionally 5 to 7% w/w of a compound of formula I,

0.5 to 50% w/w of at least one cysteine compound

can include

In some embodiments, the pharmaceutical composition

3 to 20% w/w of a compound of formula I, optionally 4 to 10% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 35% w/w of at least one cysteine compound

can include

In some embodiments, the pharmaceutical composition

3 to 20% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% w/w of at least one cysteine compound

can include

In some embodiments, the pharmaceutical composition

3 to 20% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 50% w/w of at least one cysteine compound

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

0.5 to 35% of at least one cysteine compound,

50 to 86% w/w of one or more co-solvents

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% of a cysteine compound,

50 to 86% w/w of one or more co-solvents

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% of a cysteine compound,

50 to 86% w/w of one or more co-solvents

2 to 8% w/w surfactant

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% of a cysteine compound,

50 to 86% w/w of one or more co-solvents

2-8% w/w polysorbate 80

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

0.5 to 15% w/w cysteine hydrochloride monohydrate,

0.5 to 15% w/w N -acetyl cysteine

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 15% w/w cysteine hydrochloride monohydrate,

1-15% w/w N -acetyl cysteine

50 to 86% w/w of one or more co-solvents

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, optionally 5 to 7% w/w of a compound of formula I,

1 to 15% w/w cysteine hydrochloride monohydrate,

1-15% w/w N -acetyl cysteine

50 to 83% w/w of one or more co-solvents

2 to 8% w/w surfactant

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, optionally 5 to 7% w/w of a compound of formula I

1 to 15% w/w cysteine hydrochloride monohydrate,

1-15% w/w N -acetyl cysteine

50 to 83% w/w of one or more co-solvents

2-8% w/w polysorbate 80

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w of a compound of formula I, or 5 to 7% w/w of a compound of formula I,

1 to 15% w/w cysteine hydrochloride monohydrate,

1-15% w/w N -acetyl cysteine

2-8% w/w polysorbate 80;

35 to 65% w/w PEG 400

10-30% w/w PEG 300

2 to 12% C2 to C7 alcohol

can include

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w of a compound of formula I, or 5 to 7% w/w of a compound of formula I,

1 to 15% w/w cysteine hydrochloride monohydrate,

2-8% w/w N -acetyl cysteine

2-8% w/w polysorbate 80;

35 to 65% w/w PEG 400

10-30% w/w PEG 300

2-6% w/w ethanol

2-6% w/w benzyl alcohol

can include

In some embodiments of the above example dosage forms, the pharmaceutical composition further comprises a poloxamer, eg poloxamer 188. The pharmaceutical composition may include 0.5 to 5% w/w of a poloxamer, for example poloxamer 188. The presence of a poloxamer can increase the stability of a compound of formula I, for example remdesivir.

For example, a pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% of a cysteine compound,

50 to 86% w/w of one or more co-solvents

2-8% w/w polysorbate 80

0.5 to 5% w/w Poloxamer 188

can include

For example, a pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, optionally 5 to 7% w/w of a compound of formula I,

1 to 15% w/w cysteine hydrochloride monohydrate,

1-15% w/w N -acetyl cysteine

50 to 83% w/w of one or more co-solvents

2-8% w/w polysorbate 80

0.5 to 5% w/w Poloxamer 188

can include

In some embodiments of the formulations of the above example, the pharmaceutical composition may further include a buffering agent, such as tris (ie, tromethamine). The pharmaceutical composition may include 0.25 to 5% w/w Tris.

For example, a pharmaceutical composition may include.

In some embodiments, the pharmaceutical composition

3 to 10% w/w of a compound of formula I, optionally 4 to 8% w/w, or optionally 5 to 7% w/w of a compound of formula I,

1 to 30% cysteine compound,

50 to 86% w/w of one or more co-solvents

2 to 8% w/w surfactant

0.25 to 5% w/w Tris

can include

In some examples of the above example formulations, the compound of Formula I is remdesivir.

In some embodiments, the pharmaceutical composition may include one or more antioxidants.

In some embodiments, the pharmaceutical composition has a solubility of the compound of formula I greater than 0.01 mg/mL when placed in an aqueous solution at pH 6.5, optionally greater than 0.05 mg/mL, optionally greater than 0.1 mg when placed in an aqueous solution at pH 6.5. It is formulated to have a solubility greater than /mL.

formulation

The pharmaceutical compositions described herein may be formulated as any suitable dosage form for therapeutic use.

In some embodiments, the pharmaceutical composition is an oral dosage form. Oral dosage forms include solid oral dosage forms, liquid oral dosage forms, capsules, tablets, liquid-filled capsules, which are capable of consistently delivering precise doses to achieve appropriate plasma concentrations of the compound of formula (I) that produce the intended therapeutic effect. caplets, chewable gums, oral films, oral solutions, suspensions, emulsions, lozenges, wafers, granulated powder formulations, simple powders or mixtures thereof, elixirs ) or in syrup form. In some embodiments, the tablet is an immediate release dosage form. In some embodiments, the tablet is a film-coated tablet. In some embodiments, the tablet is an orally disintegrating tablet (ODT).

In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, liquid formulations are used as injectable solutions. In some embodiments, liquid formulations are used for oral administration, such as liquid-filled capsules or oral solutions.

capsule

In another aspect, a capsule comprising the pharmaceutical composition described herein is provided. In some embodiments, the capsule is a liquid-filled capsule. In some embodiments, a liquid-filled capsule comprises a liquid formulation of a pharmaceutical composition as described herein. In one embodiment, the liquid-filled capsule has a volume of about 0.4 mL to about 0.9 mL, optionally about 0.6 mL to about 0.8 mL, optionally about 0.7 mL. In one embodiment, the capsule comprises any suitable shell. In one embodiment, the capsule is a hard gelatin capsule or soft gelatin capsule. In one embodiment, the shell comprises any suitable material such as gelatin or hypromellose.

In some embodiments, the concentration of the compound of Formula I in the liquid-filled capsule is between 30 mg/mL and 100 mg/mL, alternatively between 40 mg/mL and 80 mg/mL, alternatively between 50 mg/mL and 75 mg/mL.

oral solution

In another aspect, an oral solution comprising the pharmaceutical composition described herein is provided. In one embodiment, the oral solution comprises any liquid formulation of the pharmaceutical composition described herein, further comprising a sweetener, a common taste-masking agent, a flavor and/or a color, Additions can make the composition taste better. In one embodiment, the concentration of the active ingredient in the oral solution may be increased or decreased so that the measurement can be performed in a suitable manner depending on the conventional administration device used. Common dispensing devices include spoons, dispensing syringes, and dispensing cups. The composition may be administered in the form of a medicine, syrup, elixir, syrup or suspension.

injection

In another aspect, an injectable solution comprising a pharmaceutical composition described herein is provided, which can be further diluted using standard intravenous infusion fluids to a target concentration of active ingredient suitable for administration by intravenous infusion.

In some embodiments, the final infusion solution after dilution with a standard infusion fluid medium is also an injectable solution, which includes a pharmaceutically acceptable solvent or intravenous fluid medium. In some embodiments, the pharmaceutically acceptable solvent or intravenous fluid medium is sterile water for injection, one or more hypotonic solution(s), 0.9% sodium chloride solution (normal saline), 0.45% sodium chloride solution (1/2 normal saline), 0.225% sodium chloride solution (1/4 normal saline), and/or dextrose solutions, such as 5% dextrose (D5W). In some embodiments, the pharmaceutically acceptable solvent or intravenous fluid medium is an aqueous solution comprising from 0.8% to about 1.0% sodium chloride by weight, or about 0.9% sodium chloride by weight.

In some embodiments, the pharmaceutical composition includes a solubilizing agent. In some embodiments, a solubilizing agent is a complexing agent. Solubilizers can be selected from polymers, chelating agents, counterions (eg, suitable salt-forming counterions), or combinations thereof. Surfactants and co-solvents may also be considered solubilizing agents. In some embodiments, the solubilizing agent encapsulates the compound of Formula I and can form, for example, liposomes or micelles.

In some embodiments, the solubilizing agent is a polymer. In some embodiments, the pharmaceutical composition comprises 1, 2, 3, or 4 or more polymers. In some embodiments, a polymer may encapsulate a compound of Formula I. In some embodiments, the polymer is methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, shellac ), cellulose acetate trimetallate, sodium alginate, zein, polyvinylpyrrolidone, poly(caprolactone) (PCL), poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) ( PLA), (polyhydroxybutyrate) (PHB), poly(methicylsesquinoxane) (PMSQ), or combinations thereof. In some embodiments, the polymer is a biodegradable (eg hydrolyzable) polymer, eg PCL, PLGA, PLA or PHB. In some instances, the pharmaceutical composition comprises at least 0.1% by weight of the polymer by weight of the total pharmaceutical composition, or at least 0.5% by weight, or at least 1% by weight, or at least 5% by weight, or at least 10% by weight, or at least 20% by weight of polymer.

In some embodiments, the solubilizing agent is a suitable counterion (eg, to form a salt).

In some embodiments, the chelating agent may be selected from EDTA and salts thereof, citric acid, malic acid, malonic acid, oxalic acid, succinic acid, tartaric acid, or combinations thereof.

In some embodiments, the pharmaceutical composition includes a humectant. In some embodiments, the humectant is selected from benzalkonium chloride, poloxamers (eg, poloxamer 188, poloxamer 407), polysorbates, sodium lauryl sulfate, hypromellose, or combinations thereof.

In some embodiments, the pharmaceutical composition includes a solubilizing agent and a wetting agent. In some embodiments, a pharmaceutical composition comprising a solubilizer present in an amount of at least 0.1% (w/w) and a humectant present in an amount of at least 0.1% (w/w).

In some examples, the pharmaceutical composition comprises PEG in an amount of 30% (w/w) and hypromellose in an amount of 0.5% (w/w).

In some embodiments, the pharmaceutical composition is a compressed tablet. Compressed tablets contain one or more compression aids and bulking agents, disintegrating agents, lubricants and wetting agents. The disintegrant is cross-linked carboxymethylcellulose (croscarmellose) sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium alginate, guar gum, crosslinked polyvinylpyrrolidone or crospovidone, crosslinked starch, sodium starch glycosylate, or any combination thereof. Disintegrants can increase the rate of release from tablets and intestinal absorption of the compound of Formula I. In some embodiments, the pharmaceutical composition is in the form of a tablet comprising one or more disintegrants. In some instances, the pharmaceutical composition comprises at least 1% by weight of disintegrant, or at least 5% by weight, or at least 10% by weight, or at least 20% by weight of disintegrant by weight of the total pharmaceutical composition.

In some embodiments, the pharmaceutical composition is in the form of a tablet, wherein the tablet comprises a coating. In some embodiments, the coating comprises one or more of polyvinyl alcohol, hydroxypropylmethocellulose, hydroxypropylcellulose, ethylcellulose, shellac, alginates, acrylate polymers, color-developing ferric oxide, or any combination thereof. include In some embodiments, the pharmaceutical composition is a direct compressed tablet.

In some embodiments, the pharmaceutical composition comprises a pharmacologically acceptable excipient selected from fillers, glidants, lubricants, antioxidants, mucolytics, buffers, pH adjusters, tonicity adjusters, or combinations thereof. These excipients may be in addition to or equivalent to those described above.

In some embodiments, the filler may be selected from lactose, mannitol, sucrose, calcium sulfate, calcium phosphate, microcrystalline cellulose, xylitol, sorbitol, glucose, dextrose, mannose, maltitol, or combinations thereof.

In some embodiments, lubricants and glidants may be independently selected from fatty acids, fatty acid salts, fatty acid monoglycerides, fatty acid triglycerides, fatty acid esters, talc, silica (eg, colloidal silica), or combinations thereof. there is. Fatty acids may be saturated or unsaturated fatty acids. Fatty acids may be C ₁₀ -C ₂₂ fatty acids. In some instances, the lubricant is selected from stearic acid, magnesium stearate, sodium behenate and/or sodium stearyl fumarate.

In some embodiments, the antioxidant is selected from ascorbic acid, citric acid, sodium citrate, vitamin A, vitamin E, cysteine hydrochloride, methionine, or combinations thereof.

In some embodiments, the buffering agent is hydrochloric acid, sodium hydroxide tris, acetate, citrate, tartaric acid or salts thereof, lactic acid and salts thereof, phosphates, benzoates, bicarbonates, carbonates, sulfates, sodium chloride, potassium chloride, calcium chloride, tromethamine, or may be selected from combinations thereof. In some embodiments, the buffering agent can be Tris. Buffers may be included to improve the stability of a compound of Formula I, eg remdesivir. In some embodiments, the pharmaceutical composition comprises up to about 5% buffering agent by weight of the pharmaceutical composition, or up to about 2% buffering agent by weight of the pharmaceutical composition, or about 0.5 to about 1% buffering agent by weight of the pharmaceutical composition. can include In some embodiments, the pharmaceutical composition can comprise up to about 2% Tris by weight of the pharmaceutical composition, or about 0.5 to 1% Tris by weight of the pharmaceutical composition.

In some embodiments, the pH adjusting agent is a hydroxide (eg sodium, magnesium, calcium, potassium), a metal oxide (eg magnesium, calcium) acetic acid or a salt thereof, citric acid or a salt thereof, tartaric acid or a salt thereof, lactic acid and salts thereof, gluconic acid and salts thereof, phosphates, pyrophosphates, benzoates, bicarbonates, carbonates, sulfates, sodium chloride, potassium chloride or combinations thereof, meglumine, adipic acid, or salts thereof, tartaric acid or salts thereof, fumaric acid or a salt thereof, gluconic acid or a salt thereof, itaconic acid or a salt thereof, ammonium aluminum sulfate, ammonium bicarbonate, or ammonium hydroxide.

In some embodiments, the pharmaceutical composition in solution or as a suspension has a pH between 1 and 11. In some embodiments, the pH of the pharmaceutical composition is slightly basic, for example between 7.5 and 8. In some embodiments, the pH of the pharmaceutical composition is slightly acidic, for example less than 7, 1 to less than 7, 1.5 to 6.75, or 2 to 6.5, or 4 to 6.75, or 4 to 6.5, or 4 to less than 7, or 5 to 6.5, or 5 to less than 7, or 6 to less than 7, or 6.5 to less than 7, or 3 to 6, 4 to 6, 5 to 6, or 3 to 5, or 4 to 5, or 3 to 4. The pH of the pharmaceutical composition can alter the solubility and promote dissolution of the compound of Formula I and/or its metabolites. In some embodiments, an acidic pH promotes dissolution of the compound of Formula I.

In some embodiments, the mucolytic agent can be N-acetyl cysteine or cysteine hydrochloride.

In some embodiments, the tonicity adjusting agent may be selected from dextrose, glycerin, mannitol, potassium chloride, sodium chloride or combinations thereof.

A pharmaceutical composition described herein may comprise 10 mg to 1000 mg, or about 100 mg to 1000 mg, or about 20 mg to about 300 mg, or about 100 mg to 200 mg of Formula I. The pharmaceutical compositions described herein may contain greater than 50 mg, or 100 mg, or greater than 150 mg, or greater than 200 mg, or greater than 250 mg, or greater than 300 mg, or greater than 350 mg, or greater than 400 mg, or greater than 500 mg, or greater than 550 mg, or greater than 600 mg of Formula I. In some cases, the pharmaceutical composition may include less than 1000 mg, or less than 500 mg, or less than 200 mg. In some cases, the oral dosage of Formula I may be higher than that used for intravenous injection because of the different modes of administration. An oral dosage may include one or more tablets, for example 2 tablets, 3 tablets, or 4 tablets. An oral dosage may contain one or more capsules, for example 2, 3, or 4 capsules.

A pharmaceutical composition described herein may have a good shelf life and/or stability. The stability of the pharmaceutical compositions of the present invention can be monitored using a number of methods. Stability can be determined by determining an initial amount of compound of formula I, then measuring the amount of compound of formula I remaining after a specified period of time, and comparing the two values. The initial amount of the compound of Formula I is the amount present immediately after mixing all the ingredients of the composition. The amount of compound of Formula I present can be determined using a variety of methods known in the art, such as HPLC, mass spectrometry, spectrophotometry, gel electrophoresis, Western blotting, light scattering, microbial or other biological activity measurement assays. A typical stability tracking method consists of comparing the purity of the compound of formula I in a given product pharmaceutical composition with a freshly prepared standard in order to calculate, for any given sample, the amount of undegraded compound of formula I in the product. It can be. Samples stored and analyzed over various time periods would then provide a quantitative profile of Formula I purity over time. Optionally then, under stressful storage conditions, such as high temperatures, the rate of degradation of the compound of Formula I can then be determined by reducing the purity versus time profile by fitting a suitable regression line or curve. Such dissolution rates resulting from stressed stability studies are particularly useful for comparing different product pharmaceutical compositions over short time periods.

In certain embodiments, after storage at about 20° C. to about 25° C. for 30 days, at least 90% by weight of the compound of Formula I is present in the pharmaceutical composition, based on the initial amount of the compound of Formula I in the pharmaceutical composition. For example, after storage at about 20° C. to about 25° C. for 30 days, at least 92%, or at least 94%, or at least 96%, or at least 98%, based on the original amount of the compound of Formula I in the pharmaceutical composition. A compound of formula I exists. In some instances, the composition is stored at about 25°C, or about 24°C, or about 23°C, or about 22°C, or about 21°C. The purity of the composition according to the present invention can be monitored using one or more analytical methods from those listed above, which are most suitable for the compound of formula (I) in question. Loss of purity can be determined by subtracting the purity of the compound of Formula I in the product at any given time from the purity immediately after preparation of the product (time t ₀ ). Differences in purity may constitute a loss of purity over the duration of the test. Alternatively, the purity of a compound of Formula I can be determined at various time points from samples representing unit dosage forms prepared and stored in suitable hermetically sealed containers. The purity is then plotted against time and fitted to a regression line to determine the overall quasi-first-order degradation rate from the slope of that regression line, if linear.

The pharmaceutical compositions described herein have good bioavailability. In some embodiments, the pharmaceutical compositions described herein have good bioavailability when administered orally. In some embodiments, the bioavailability is at least 2.5%, or at least 3%, or at least 3.5%, or at least 3.5%, of the active ingredient or a metabolite formed in the body as a result of enzymatic action on the active ingredient, compared to when administered intravenously. at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8%, or at least 8.5%, or at least 9%, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. In this case, oral bioavailability is defined as AUC [(oral)/AUC(IV)] * 100.

Methods of treating viral infections

In a second aspect, a method for treating a viral infection is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the pharmaceutical compositions described herein. In some embodiments, the viral infection is an RNA viral infection.

In some embodiments, the virus causing the viral infection is a human-disease causing virus. In some embodiments, the virus is a coronavirus, respiratory syncytial virus, Ebola, hepatitis, Junin, Lassa fever, orthomyxovirus, hepatitis virus (HV) type, disease-causing picornavirus, Ebola, SARS, MERS, respiratory syncytial virus and other pneumoviruses, influenza, polio and retroviruses including adult human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV).

In some embodiments, an RNA virus may be a coronavirus. In some embodiments, the coronavirus is a coronavirus that causes disease in humans. In some embodiments, the virus may be a coronavirus that causes disease in non-human animal species, such as feline infectious peritonitis virus, porcine deltacorona virus.

In some embodiments, the viral infection is a coronavirus infection. Coronavirus infection can be caused by any type or strain of coronavirus. In some embodiments, the coronavirus infection can be an alpha coronavirus infection or a beta coronavirus infection, preferably a beta coronavirus infection. Beta coronaviruses can have an A strain, a B strain, a C strain or a D strain, for example a B strain. In a preferred embodiment, the coronavirus infection may be COVID-19, otherwise known as SARS-CoV-2 or 2019-nCoV.

In some embodiments, the pharmaceutical compositions described herein may be administered for prophylactic use to prevent infection under circumstances where there is a foreseeable risk of infection, or at least to prevent severe symptoms of a disease.

In some embodiments, the pharmaceutical composition may be administered using any suitable method of administration. In one embodiment, the pharmaceutical composition is administered orally, parenterally, by inhalation or nebulization, or by intratracheal instillation. In one embodiment, the pharmaceutical composition is administered to target delivery of the compound of Formula I to the site of viral infection, eg to the lungs, eg to alveolar cells in the case of SARS-CoV-2. Targeted drug delivery refers to any method of drug delivery that increases drug concentration in some parts of the body relative to other parts. In some embodiments, the pharmaceutical composition can be administered by injection. In some embodiments, the injection can be intravenous or subcutaneous. In some cases, subcutaneous injection may be advantageous because it is often non-invasive, safe, well tolerated, and/or requires reduced resource use due to reduced need for specialized skills or monitoring during administration.

In some embodiments, the pharmaceutical composition can be administered orally.

In some embodiments, the pharmaceutical composition described herein is administered less than 4 days after exposure to a COVID-19 case (eg, another positive case), or less than 3 days after exposure to a COVID-19 case, or It may be administered within less than 2 days after exposure, or within 1 day after exposure, or within 1 hour after exposure.

In some embodiments, the pharmaceutical compositions described herein are used, primarily for the purpose of prophylactic prevention of infection, to prevent possible exposure of viruses to otherwise healthy individuals who do not have any notable signs or symptoms of disease. can be administered.

In some embodiments, the pharmaceutical composition described herein is used to treat symptoms caused by COVID-19, i.e. cough, sore throat, fever or fever, loss of smell or taste, shortness of breath, fatigue, myalgia, chest pain, runny nose, headache, chills, or any combination thereof.

In some embodiments, the viral infection is a hepatitis infection. Hepatitis infection can be hepatitis A, B, C, D or E. Hepatitis infection can be acute hepatitis, fulminant hepatitis or chronic hepatitis.

In some embodiments, the pharmaceutical composition described herein is administered every 4 hours to every 4 weeks. In one embodiment, the pharmaceutical composition described herein is administered every 4 hours, or up to every 8 hours, or up to every 12 hours, or up to every 16 hours, or up to every 24 hours, or up to every 48 hours, or up to every 36 hours. hour, or up to every 72 hours, or up to every 144 hours, or up to every week, or up to every 2 weeks, or up to every 4 weeks. If the symptoms are more severe, the compound of Formula I may be administered more frequently. An effective amount of a pharmaceutical composition described herein can be administered in either single or multiple doses. Multiple doses can be administered simultaneously or at different times during the day (eg, once, twice, three times, four times, five times, or even six times per day).

The amount (i.e., dosage) of the compound administered depends on the particular viral infection being treated, the mammal being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, the bioavailability of the particular compound, and its effectiveness for the particular viral infection being treated. It depends on the inhibitory concentration (IC ₅₀ ). In one embodiment, the dosage of the compound of Formula I is about 2 to 20 mg/kg, eg 3 to 18 mg/kg, 5 to 15 mg/kg, 7 to 14 mg/kg or 10 to 12 mg/kg. kg.

In some embodiments, the pharmaceutical composition is a liquid formulation. In some embodiments, the amount of liquid formulation administered is between about 1 mL and about 40 mL of a liquid formulation, for example between about 3 mL and about 35 mL, or between about 5 mL and about 30 mL, or between about 10 mL and about 30 mL, or about 10 mL to about 25 mL, or about 15 mL to about 25 mL. In some embodiments, the amount of a compound of Formula I administered to a subject is between 10 and 1000 mg, or between 20 and 300 mg, or between 100 and 200 mg of a compound of Formula I. In some embodiments, liquid formulations are administered as liquid-filled capsules as described herein. In some embodiments, more than one liquid-filled capsule is administered to a subject, or more than two, more than three, or more than four liquid-filled capsules are administered to a subject.

In some embodiments of the method, the compound of Formula I is metabolized to an active metabolite (triphosphate-Compound D) such that the active metabolite is present in peripheral blood cells and/or target tissues in an amount of at least 0.02 μM, or at least 0.04 μM, or at a concentration of at least 0.06 μM, or at least 0.08 μM, or at least 0.1 μM, or at least 0.15 μM.

In some embodiments of the method, the compound of Formula I is metabolized to an active metabolite (triphosphate-Compound D) such that the peak concentration of the active metabolite is at least 0.5 μM, or at least 0.7 μM in peripheral blood cells and/or target tissue. μM, or at least 1 μM, or at least 10 μM.

[Compound D]

In some embodiments of the method, the bioavailability of the compound of formula I after administration, as measured with respect to the compound of formula I or any direct metabolite thereof, such as compound C [GS-441524], in the blood versus the time curve at least 3%, or at least 5%, or at least 7%, or at least 10%, or at least 50%, or at least 80%, or at least 90%, as measured by area under plasma concentration (AUC).

In some embodiments of the method, the bioavailability of Formula I in peripheral blood cells after administration, as measured with respect to Compound D, is at least as measured by the area under concentration in peripheral blood cells (AUC) versus time curve. 3%, or at least 5%, or at least 7%, or at least 10%, or at least 50%, or at least 80%.

In some embodiments of the method, the bioavailability of the compound of Formula I after oral administration is at least 2.5%, or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, compared to intravenous administration. or at least 5%, or at least 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8%, or at least 8.5%, or at least 9%, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%.

In some embodiments of the method, the oral bioavailability of Compound C (i.e., the nucleoside analog GS-441524) is measured relative to an intravenous dose of the Compound of Formula I and in the blood following oral administration of the Compound of Formula I. at least 2.5%, or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least as compared to intravenous administration of the compound of Formula I, as measured from the concentration of Compound C 5.5%, or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8%, or at least 8.5%, or at least 9%, or at least 9.5%, or at least 10%, or at least 12.5%, or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 60%, or at least 70% %, or at least 80%.

In some embodiments of the method, Compound D (i.e., the active triphosphate salt, as measured against the intravenous dose of the Compound of Formula I and determined from the concentration of Compound D in peripheral blood cells following oral administration of the Compound of Formula I). ) is at least 2.5%, or at least 3%, or at least 3.5%, or at least 4%, or at least 4.5%, or at least 5%, or at least 5.5%, compared to intravenous administration of the compound of Formula I. , or at least 6%, or at least 6.5%, or at least 7%, or at least 7.5%, or at least 8%, or at least 8.5%, or at least 9%, or at least 9.5%, or at least 10%, or at least 12.5% , or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%.

This disclosure may be described by one or more of the following clauses:

A. Oral Formulations Comprising the Compound of Formula I:

[Formula I]

wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester, O-linked carbamate, S-linked phosphothioate, or N -selected from linked phosphoramidites).

B. The oral dosage form of item A, wherein the compound of Formula I is a prodrug.

C. The oral dosage form of item A, wherein X is an O-linked phosphoramidite or an O-linked phosphoester.

을 갖는 O-연결된 포스포아미다이트이며,D. The compound of any one of paragraphs A-C, wherein X is of the formula

It is an O-linked phosphoramidite having

Here, R ₂ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, methyl glumine, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H or C ₁ -C ₆ alkyl;

R ₄ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl, oral formulations.

E. The oral dosage form of item D, wherein R ₃ is methyl.

을 갖는 O-연결된 포스포아미다이트이며,F. The compound of any one of A-C, wherein X is of the formula

It is an O-linked phosphoramidite having

wherein R ₂ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglu Min, procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl;

R ₃ is H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, phenyl;

R ₄ is H, lithium, sodium, potassium, aluminum, ammonium, arginine benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, tromethamine, meglumine , procaine, trimethylamine, zinc, C ₁ -C ₆ alkyl, C ₂ -C ₆ -allyl, C ₂ -C ₆ alkenyl, phenyl, biphenyl, heteroaryl, oral formulations.

인, 경구 제형.G. A compound according to any one of items A to F, wherein the compound of formula I

Phosphorus, oral dosage form.

H. The oral dosage form of item A, wherein X is hydroxyl, metal salt hydroxylate, O-linked ester or O-linked carbamate.

I. The oral dosage form of paragraphs A or H, wherein the O-linked ester is an O-linked amino acid or an O-linked peptide.

J. The oral dosage form of item I, wherein the O-linked amino acid or O-linked peptide is formed from amino acids selected from alanine, valine, leucine, isoleucine, glycine, isoleucine, tyrosine, tryptophan or combinations thereof.

K. The oral dosage form of any one of paragraphs A-J, wherein the compound of formula I has a logP of less than 2.

L. The oral dosage form of any one of paragraphs A-K, wherein the compound of formula I has a logS greater than -2.

M. The oral formulation of any one of paragraphs A to L, wherein the metabolized active product of the compound of formula I is compound D:

[Compound D]

.

.

N. The oral dosage form of any one of A to M, wherein the oral dosage form is a solid oral dosage form, liquid oral dosage form, capsule, tablet, liquid-filled capsule, caplet, chewable gum, oral film, oral solution, suspension, Oral dosage forms, in the form of emulsions, lozenges, wafers, granulated powder formulations, simple powders or mixtures thereof, elixirs or syrups.

O. The oral dosage form of any one of paragraphs A-N, which is free of cyclodextrin.

P. The oral dosage form of any one of paragraphs A to O, further comprising a solubilizing agent.

Q. The oral dosage form of item P, wherein the solubilizing agent encapsulates the compound of Formula I.

R. The oral dosage form of any one of P or Q, wherein the solubilizing agent is selected from liposomes, micelles, polymers, surfactants, cosolvents, chelating agents, counterions, or combinations thereof.

S. The method of R, wherein the solubilizing agent is a polymer, wherein the polymer is methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate. , polyvinyl acetate phthalate, shellac, cellulose acetate trimetalate, sodium alginate, zein, polyvinylpyrrolidone, poly(caprolactone), poly(lactic-co-glycolic acid), poly(lactic acid), poly(hydride) oxybutyrate), poly(methylsilsesquioxane), or combinations thereof.

The method of T.S, wherein the polymer is a biodegradable polymer, optionally selected from poly(caprolactone), poly(lactic-co-glycolic acid), poly(lactic acid) and/or poly(hydroxybutyrate). Oral formulation.

U.R., wherein the solubilizing agent is a cosolvent, wherein the cosolvent is PEG, glycerol, glycofural, DMSO, ethanol, propylene glycol, methyl lactate, ethyl lactate, propyl lactate, spironolactone, N-methyl Pyrrolidone, Benzyl Alcohol, Cetostearyl Alcohol, Benzyl Benzoate, Corn Syrup, Acacia Syrup, Glucose Syrup, Acetyl Tributyl Citrate, Lactic Acid, Acetic Acid, Ethyl Acetate, Benzoic Acid, Polyoxyl 35 Castor Oil, Polysorbate 20 , 40, and 80; water; mineral oil, hydrogenated edible oil; An oral formulation selected from edible unhydrogenated cooking oils or combinations thereof.

V. The method of R, wherein the solubilizing agent is a counter ion, wherein the counter ion is a metal ion, wherein the metal ion is Ag ⁺ , Fe ²⁺ , Fe ³⁺ , Co ²⁺ , Co ³⁺ , Cu ²⁺ , Zn ²⁺ , or a combination thereof.

W. The oral dosage form of R, wherein the solubilizing agent is a chelating agent, wherein the chelating agent is selected from EDTA and salts thereof, citric acid, malic acid, malonic acid, oxalic acid, succinic acid, tartaric acid, or combinations thereof.

X. The composition of any one of paragraphs A-W, wherein benzalkonium chloride, poloxamer (e.g. poloxamer 188, poloxamer 407), polysorbate, sodium lauryl sulfate, hypromellose or combinations thereof An oral dosage form further comprising one or more humectants selected from

Y. The cross-linked carboxymethylcellulose (croscarmellose) sodium, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium alginate, guar gum, crosslinked polyvinylpyrroly according to any one of items A to X. The oral dosage form, further comprising one or more disintegrants selected from pork or crospovidone, crosslinked starch, sodium starch glycosylate, or any combination thereof.

Z. The method of any one of paragraphs A to Y, wherein the oral dosage form is a tablet, wherein the tablet is polyvinyl alcohol, hydroxypropylmethocellulose, hydroxypropylcellulose, ethylcellulose, shellac, alginate, acrylate polymer, oxidized An oral dosage form comprising a coating comprising one or more of ferric iron or a combination thereof.

AA. The method of any one of items A to Z, wherein one or more pharmacologically acceptable excipients selected from fillers, glidants, lubricants, antioxidants, mucolytics, buffers, pH adjusting agents, tonicity adjusting agents, or combinations thereof are added. Oral formulations comprising as.

BB. The oral dosage form of AA, wherein the filler is selected from lactose, mannitol, sucrose, calcium sulfate, calcium phosphate, microcrystalline cellulose, xylitol, sorbitol, glucose, dextrose, mannose, maltitol, or combinations thereof.

CC. The oral formulation of paragraph AA, wherein the lubricant is selected from vegetable oils, animal oils, fatty acids, fatty acid salts, fatty acid monoglycerides, fatty acid triglycerides, talc, silica, or combinations thereof.

DD. The oral dosage form of AA, wherein the antioxidant is selected from ascorbic acid, citric acid, sodium citrate, vitamin A, vitamin E, cysteine hydrochloride, methionine, or combinations thereof.

E.E. The oral dosage form of any one of paragraphs A to DD comprising between 10 mg and 1000 mg of a compound of Formula I, or between about 100 mg and 1000 mg of a compound of Formula I.

FF. A method of treating an RNA viral infection comprising orally administering to a subject in need thereof a therapeutically effective amount of the oral formulation of any one of items A to Z or AA to EE.

G.G. The method of claim FF, wherein the viral infection is a coronavirus infection.

HH. The method of clause FF, wherein the coronavirus infection is COVID-19.

II. The method of claim FF, wherein the viral infection is a hepatitis infection.

JJ. The method of any one of paragraphs FF-II, wherein the oral dosage form is administered every 4 hours to every 4 weeks.

K.K. The method according to any one of claims FF to JJ, wherein the compound of formula I is metabolized to an active metabolite of compound D such that the active metabolite is present in peripheral blood cells and/or target tissue in a concentration of at least 0.1 μM. .

[Compound D]

LL. The method of any one of claims FF to KK, wherein the bioavailability of the compound of formula I after oral administration is at least 5%.

This disclosure may also be described by one or more of the following terms:

a. A pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable excipient selected from cysteine compounds, amino acids, amino acid salts, N -acetyl amino acids, organic acids or salts thereof, or any combination thereof:

[Formula I]

wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester, O-linked carbamate, S-linked phosphothioate, or selected from N-linked phosphoramidites).

b. The pharmaceutical composition of item a, wherein the pharmaceutical composition is free of cyclodextrin.

c. The pharmaceutical composition according to item a or b, wherein the composition is a solution, suspension or a mixture thereof.

d. The pharmaceutical composition according to any one of items a to c, wherein the pharmaceutical composition is an oral dosage form or a parenteral dosage form.

e. The method of any one of items a to d, wherein the at least one pharmaceutically acceptable excipient comprises an acid or a salt thereof, optionally the acid is lactic acid, acetic acid, adipic acid, citric acid, formic acid, succinic acid, oxalic acid, ascorbic acid An organic acid selected from acid, uric acid, malic acid, tartaric acid, or any combination thereof.

f. The pharmaceutical composition according to any one of items a to e, wherein the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound.

g. The pharmaceutical composition of claim f, wherein the % w/w ratio of the at least one cysteine compound to the compound of formula I is at least 1:1, optionally greater than 1.5:1.

h. According to any one of items f to g,

a. 0.05 to 20% w/w of a compound of Formula I and

b. 0.5 to 50% w/w of at least one cysteine compound

A pharmaceutical composition comprising a.

i. According to any one of items f to h,

a. 4 to 8% w/w of a compound of formula I, optionally 5 to 7% w/w of a compound of formula I and

b. 1 to 30% w/w of at least one cysteine compound

A pharmaceutical composition comprising a.

j. The pharmaceutical composition according to any one of items f to i, wherein the at least one cysteine compound comprises cysteine, glutathione, cysteine hydrochloride and/or N -acetyl cysteine or combinations thereof.

k. The pharmaceutical composition according to any one of items f to j, wherein the at least one cysteine compound is cysteine hydrochloride and/or N -acetyl cysteine.

l. The pharmaceutical composition according to any one of items f to k, wherein the at least one cysteine compound is cysteine hydrochloride and N -acetyl cysteine.

m. According to any one of items f to l,

a. 3 to 10% w/w of a compound of formula I

b. 0.5 to 15% w/w cysteine hydrochloride monohydrate

c. 0.5 to 15% w/w N -acetyl cysteine

A pharmaceutical composition comprising a.

n. The pharmaceutical composition according to any one of items a to m, wherein the pharmaceutical composition is a liquid dosage form.

o. The pharmaceutical composition according to claim n, wherein the pharmaceutical composition comprises one or more co-solvents.

p. The pharmaceutical composition according to any one of items n to o, wherein the liquid formulation has a pH less than 8.5, optionally the pH ranges from 1 to less than 8.

q. According to any one of items n to p,

a. 3 to 10% w/w of a compound of formula I

b. 0.5 to 30% w/w of a cysteine compound

c. 50 to 86% w/w of one or more co-solvents

A pharmaceutical composition comprising a.

r. According to items n to q,

a. 3 to 10% w/w of a compound of formula I

b. 1 to 15% w/w cysteine hydrochloride monohydrate,

c. 3-15% w/w N -acetyl cysteine

d. 50 to 86% w/w of one or more co-solvents

A pharmaceutical composition comprising a.

s. The pharmaceutical composition according to items n to r, wherein the one or more co-solvents are selected from PEG, benzyl alcohol, ethanol or combinations thereof.

t. The pharmaceutical composition of items n-s, wherein the one or more co-solvents comprises low molecular weight polyethylene glycol (PEG), propylene glycol, benzyl alcohol, ethanol or combinations thereof.

u. The pharmaceutical composition according to item t, wherein the PEG has a molecular weight of 200 to 1000.

v. The pharmaceutical composition according to any one of items a to u, comprising one or more surfactants.

w. The method of item v, wherein the one or more surfactants are polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl 35 castor oil, cremophor, polyoxyethylene (20) sorbitan monool poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers such as poloxamers, or combinations thereof A pharmaceutical composition selected from.

x. The pharmaceutical composition according to any of items v to w, wherein the at least one surfactant has an HLB value of 10 to 20, optionally 12 to 18, or optionally 14 to 16.

y. The pharmaceutical composition of any one of v-x, wherein the at least one surfactant is polysorbate.

z. According to any one of items v to y,

a. 3 to 10% w/w of a compound of formula I

b. 1-15% w/w cysteine hydrochloride monohydrate

c. 3-15% w/w N -acetyl cysteine

d. 50 to 83% w/w of one or more co-solvents

e. 2 to 8% w/w surfactant

A pharmaceutical composition comprising a.

aa. According to any one of items x to z,

a. 3 to 10% w/w of a compound of formula I

b. 1-15% w/w cysteine hydrochloride monohydrate

c. 3-15% w/w N -acetyl cysteine

d. 4-8% w/w polysorbate 80

e. 35-60% w/w PEG 400

f. 10-30% w/w PEG 300

g. % w/w ethanol

h. Benzyl alcohol in % w/w

A pharmaceutical composition comprising a.

bb. The pharmaceutical composition according to any one of items a to aa, comprising one or more antioxidants.

cc. The pharmaceutical composition according to any one of items a to bb, wherein the metabolized active product of the compound of formula I is compound D.

[Compound D]

또는

인, 화합물.ee. According to any one of items a to cc, the compound of formula I is

or

phosphorus, compounds.

gg. The pharmaceutical composition according to any one of items a to ff, wherein the pharmaceutical composition is formulated to have a solubility of greater than 0.05 mg/mL when the compound of formula I is placed in an aqueous solution at pH 6.5.

hh. A method of treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of items a to gg.

ii. According to item hh, the virus causing viral infection is a coronavirus, respiratory syncytial virus, Ebola, hepatitis, Junin, Lassa fever, orthomyxovirus, hepatitis virus (HV) type, disease-causing picornavirus, Ebola, SARS , MERS, respiratory syncytial virus and other pneumoviruses, influenza, polio and retroviruses including adult human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV), method.

jj. The method of claim hh, wherein the viral infection is a coronavirus infection.

kk. The method of jj, wherein the coronavirus infection is SARS-CoV-2.

ll. The method of any one of clauses hh to jj, wherein the amount of compound of Formula I administered is from about 20 mg to about 300 mg, or from about 50 mg to 250 mg.

mm. The method of any one of clauses hh to ll, wherein the pharmaceutical composition is a liquid formulation, and optionally the amount of liquid formulation administered is from about 1 mL to about 40 mL of an undiluted liquid formulation.

nn. The method according to any one of claims hh to mm, wherein the pharmaceutical composition is administered orally.

oo. The method of any one of claims hh to nn, wherein the pharmaceutical composition is administered by injection.

pp. The method of use according to item oo, wherein the injection is an intravenous or subcutaneous injection.

qq. The method of use according to item pp, wherein the injection is an intravenous or subcutaneous injection administered after dilution with an intravenous infusion to a final infusion of 100 to 250 mL.

rr. A capsule comprising the pharmaceutical composition of any one of items a to gg.

ss. The capsule according to item rr, wherein the capsule is a liquid filled capsule.

tt. ss, wherein the liquid-filled capsule has a volume of about 0.4 mL to about 0.9 mL, optionally about 0.6 mL to about 0.8 mL, optionally about 0.7 mL.

uu. An oral solution comprising the pharmaceutical composition of any one of items a to gg.

vv. An injectable solution comprising the pharmaceutical composition of any one of items a to gg.

Example

Effect on solubility of pharmaceutical excipients

Various compounds were tested in combination with remdesivir to see whether the compound had a solubilizing effect. The present inventors have specifically found that cysteine-compounds (eg, cysteine hydrochloride, N-acetyl cysteine, L-cysteine and glutathione) all exhibit a solubilizing effect on remdesivir, and all at concentrations suitable for administration. Solubility was greater than 0.01 mg/mL for cysteine-related compounds. Furthermore, certain cysteine compounds, namely cysteine hydrochloride and N-acetyl cysteine, have been shown to improve remdesivir solubility to greater than 0.2 mg/mL at excipient concentrations suitable for administration by oral and parenteral routes. Without wishing to be bound by theory, it is believed that in addition to any inherent effect on solubility, the improvement in the solubility of remdesivir in solutions of cysteine hydrochloride and N-acetyl cysteine is also due to the slight acidifying effect of these compounds. it could be

Both N-acetyl amino acids, such as N-acetyl cysteine and N-acetyl D-alanine, also showed significant solubilization effects.

Pharmaceutical excipients and their effect on remdesivir solubility at concentrations of these excipients in water that can be defined by the maximum daily intake (MDI) for each excipient Remdesivir solubility (mg/mL) DL-Tyrosine 0.001 Plasdon, PVP 0.003 L-Arginine 0.000 tromethamine 0.000 cysteine hydrochloride 0.546 D-sorbitol 0.008 meglumine 0.000 hypromellose 0.004 N-acetyl-D-alanine 0.082

CD)Cavitron (HP

CD) 0.050 L-cysteine 0.010 N-acetyl-L-cysteine 0.236 sodium sulfide 0.000 sodium sulfate 0.002 sodium sulfite 0.000 L-Methionine 0.000 L-Glutathione 0.03 monothioglycerol 0.004 sodium saccharin 0.0005

†MDI or maximum daily intake is based on the FDA IIG database for approved oral dosage forms when diluted in 250 mL of water. It is intended to reflect the final concentrations of these excipients that can be achieved in the intestine when the maximum approved intake is administered with the daily dose of the drug.

Due to the good results observed with cysteine HCl and N-acetyl cysteine, they were compared to sulfobutylether β cyclodextrin (SBE β CD), a known excipient used in remdevicir formulations. The concentration of SBE β CD used was 11.8 mg/mL, which corresponds to approximately 3 g of SBE β CD dissolved in 250 mL of intestinal fluid, which is equivalent to 100 mg of remdesivir in a commercially available lyophilized injectable formulation. Approximately the same amount of SBE β CD (3 g) used for Vir. As can be seen in Table 2, both cysteine hydrochloride and N-acetyl cysteine solubilized remdesivir more effectively than SBE β CD on a weight basis. This is because the pharmaceutical compositions described herein can be used to solubilize and administer remdesivir to improve oral bioavailability, or to patients with compromised kidneys who are unable to receive current products containing large amounts of SBE β CD. This indicates that it may provide an alternative strategy for administering vir intravenously.

Comparison of cysteine HCl and N-acetyl-L-cysteine with sulfobutylether β cyclodextrin excipient Concentration in water (mg/mL) Remdesivir solubility (mg/mL) Cysteine HCl 20 0.91 Cysteine HCl 14 0.81 Cysteine HCl 9.3 0.55 Cysteine HCl 5 0.39 N-acetyl-L-cysteine 14 0.24 N-acetyl-L-cysteine 11 0.18 Sulfobutylether β cyclodextrin 11.8 0.05

Effect of pH on Remdesivir Solubility

To test the effect of pH and acidity on remdesivir solubility, the solubility of remdesivir was screened in various acids. The results presented in Table 3 indicate that the solubility of remdesivir is increased in the presence of acid at lower pH. This indicates that organic acids and other acidulants can improve solubilization and dissolution of remdesivir from oral dosage forms.

menstruum pH (range) Solubility (mg/mL) hydrochloric acid solution 0.98 2.49 hydrochloric acid solution 0.38 0.98 hydrochloric acid solution 1.89 0.34 hydrochloric acid solution 2.91 0.005 hydrochloric acid solution 4.74 0.0010 hydrochloric acid solution 6.18 0.0009 hydrochloric acid solution 6.72 0.00 1 M acetic acid solution 1.5 0.32 boric acid solution 3.5 0.01 1 M citric acid solution 0.5~1.0 0.95 1 M ascorbic acid solution 1.0 to 1.5 0.64 1 M tartaric acid solution 0.5~1.0 1.69 1 M lactic acid solution 1.5 0.74 1 M formic acid solution 1.5 0.89

To determine the stability of the prodrug remdesivir at different pHs, the stability of the prodrug remdesivir was tested over time at pHs physiologically relevant to the gastrointestinal medium. Degradation of remdesivir was determined by measuring the unchanged amount of remdesivir using a suitable high pressure liquid chromatography (HPLC) method and comparing the result to a pure reference sample of remdesivir. As shown in Figure 1, the results show acceptable stability and minimal degradation at a pH of 3 to 9.

Effect of co-solvent on solubility

Various co-solvents were screened for their dissolution effect on remdesivir and the results are shown in Table 4.

menstruum Solubility (mg/mL) N-methyl-2-pyrrolidone (NMP) ≥112 Soluplus ^® + Ethanol + Water ≥34 Plasdone (PVP) + PEG 300 ≥66 NMP + ethanol ≥226 ethanol ≥21 benzyl alcohol ≥56 propylene glycol ≥29 PEG 300 ≥39 PEG 400 ≥16 PEG 600 ≥6.2 PEG 1000 ≥6.3 PEG 400 + glycerol (3:5) 0.011 PEG 400 + glycerol (3:100 0.0008 castor oil 0 Sesame oil 0 Peppermint Oil 15.9 soybean oil 0 peanut oil - mineral oil - Span 80 0.3 span 20 0.006

The results show that, due to solubilization using a suitable combination of co-solvent and solubilizing excipient, it is possible to maintain the solubility of remdesivir in various gastrointestinal media that may be encountered throughout the course of oral administration followed by subsequent gastric transit and intestinal absorption. Proven. Because only dissolved drug components are absorbed, sustained solubility is important for poorly soluble and slowly soluble molecules such as remdesivir to maximize bioavailability. Similarly, the above data demonstrates that certain combinations of co-solvents and solubilizing excipients may be useful in formulating injectable dosage forms that do not contain SBE β CD.

Effect of surfactant on solubility

Surfactants HLB value Concentration in water (% w/w) Remdesivir solubility (mg/mL) Tween 20 (Polysorbate 20) 16.7 0.16 0.016 Tween 80 (Polysorbate 80) about 15 0.30 0.033 Poloxamer P188 about 29 0.07 0.000 Poloxamer P407 about 18 0.07 0.006 Collipore EL (Polyoxyl 35 Castor Oil; Cremophor) about 15 0.10 0.020

Remdesivir solubility was also tested in the presence of various surfactants, with the best results being obtained with polysorbate and polyoxyl castor oil surfactants (both HLB values of 15).

pharmaceutical composition

Based in part on the above-mentioned solubility and stability studies at different pH, the present inventors developed the following example pharmaceutical compositions. Remdesivir was found to dissolve effectively in the pharmaceutical compositions of these Examples. Furthermore, Example Pharmaceutical Composition 1 showed good results in subsequent dissolution and solubility tests.

Example Pharmaceutical Composition 1 - ES040-36 ingredient %(w/w) intake/100 mg dose Remdesivir 7 100 mg Cysteine hydrochloride monohydrate 6 85.7 mg (59.1 mg of cysteine) N-acetyl-L-cysteine 6 85.7mg Tween 80 (Polysorbate 80) 6 85.7mg PEG 300 16 228.6mg PEG 400 53 757.1mg ethanol 4 78.3mg benzyl alcohol 4 81.1mg

Example Pharmaceutical Composition 2 - ES040-32A ingredient %(w/w) intake/100 mg dose Remdesivir 5 100 mg Cysteine hydrochloride monohydrate 12 240 mg (165.6 mg of cysteine) N-acetyl-L-cysteine 8 160mg Tween 80 (ie Polysorbate 80) 6 120 mg PEG 300 20 400 mg PEG 400 43 860mg ethanol 4 80 mg benzyl alcohol 4 80 mg

Example Pharmaceutical Composition 3 - ES040-86 ingredient %(w/w) intake/100 mg dose Remdesivir 6.7 100 mg Cysteine hydrochloride monohydrate 2.08 31.0mg N-acetyl-L-cysteine 6.07 90.6mg Tween 80 (ie Polysorbate 80) 5.70 85.1mg PEG 300 16.02 239.1mg PEG 400 53.38 796.7mg ethanol 4.07 60.7mg benzyl alcohol 4.02 60mg Tromethamine (Tris) 0.71 10.6mg Poloxamer P188 1.23 18.4mg

Example Pharmaceutical Composition 4 - ES040-90 ingredient %(w/w) intake/100 mg dose Remdesivir 6.7 100 mg Cysteine hydrochloride monohydrate 3.33 49.7mg N-acetyl-L-cysteine 6.22 92.8mg Tween 80 (ie Polysorbate 80) 6.01 89.7mg PEG 300 16.46 245.7mg PEG 400 55.03 821.3mg ethanol 0 0mg benzyl alcohol 4.11 61.3mg Poloxamer P188 2.15 32.1mg

Dissolution and solubility studies

The solubility and/or dissolution of remdesivir over time was determined for various pharmaceutical compositions using a Type II dissolution apparatus. Regarding the dissolution and release of liquid formulations filled into hard gelatin capsules and "as is", i.e., not filled into capsule shells, unformulated powdered drug substances filled into capsules, and the combination thereof with the solubilizing complexing agent SBE β CD compared. The dissolution profile was compared to that of the acetaminophen drug substance filled into hard gelatin capsules. Acetaminophen has a bioavailability of over 80% in practice. 100 rpm using 15 mg of remdesivir in 300 mL of a dissolution medium comprising a 0.4% solution of Tween 80 in water, which was previously determined to provide sufficient solubility of remdesivir for a test dose of 15 mg. The dissolution test was performed at stirring speed. At appropriate time intervals, aliquots of approximately 1 mL of the dissolution medium were withdrawn, filtered, and tested for remdesivir using a high-pressure chromatography assay. The area under the peak for the drug at the standard elution time is then compared to the area of an external reference standard of remdesivir to determine the concentration of remdesivir dissolved at any given time.

Specifically, Example Formulation 1 (ES040-36) containing remdesivir as a solution added directly into a dissolution medium without filling into a capsule shell and also filled into a hard gelatine capsule to exhibit release from an oral solution. tested. The example formulations were compared to the solid form of remdesivir in capsules without excipients or in the presence of SBE β CD, a solubilizing excipient used in currently marketed infused formulations as a reference example.

The research results are shown in FIG. 2 . The data values of the diamond shape correspond to the pharmaceutical composition of the present invention. broken hollow diamonds indicate dissolution of the composition when the composition is added directly to the dissolution medium as a liquid phase rather than filled into a hard gelatine capsule; Solid diamonds indicate dissolution of the composition when the composition is filled into hard gelatin capsules and then added to the dissolution medium. The data values in circles with thin dashed lines correspond to a different active ingredient, acetaminophen, for comparison, showing the dissolution profile of the drug with high bioavailability. Comparative controls included powdered bulk acetaminophen drug substance filled into hard gelatin capsules. The square data values represent the dissolution of the remdesivir drug substance as a powder filled into either hard gelatin capsule, with or without any other excipients (solid squares), with or without the solubilizing excipient, SBE β CD (hollow squares).

In the absence of pharmaceutical excipients, remdesivir exhibited very slow dissolution in a dissolution medium selected to create and maintain a sink state for the drug. A dissolution medium comprising 0.4% Tween 80 in water was previously determined to provide adequate solubility for the dose of remdesivir selected for dissolution testing. The submerged state is the solubility of remdesivir in the medium such that a concentration gradient is created between a saturated solution at the surface of the dissolving drug particle and the bulk of the dissolution medium in order to cause the drug molecules to diffuse into the bulk away from the dissolving particle surface. is guaranteed to be sufficient. Despite such submerged conditions, the remdesivir drug substance in capsules (FIG. 2; "Remdesivir in capsules") was comparable to the control acetaminophen with high oral bioavailability (FIG. 2; "Acetaminophen API in capsules"). Performance was not much better by comparison. For oral formulations of drugs with very poor solubility, such as remdesivir, a slow rate of dissolution will reduce the rate of absorption and take away the precise time span available for absorption from the intestine, resulting in lower oral bioavailability .

In contrast, both Example Formulation 1 (ES040-36) were added directly as a solution (see Figure 2, diamond data values with dashed lines, "ES050-36 without capsule") and when filled into hard gelatin capsules (Figure 2). 2, diamond data values with solid lines, “ES050-36 in capsules), significantly improved the dissolution rate and rapidly reached the maximum concentration of remdesivir in the dissolution medium.

The above results demonstrate that the pharmaceutical composition described herein can increase the solubility and dissolution rate of remdesivir compared to the addition of API in capsules and SBE β CD, a solubilizing excipient used in currently marketed formulations. As a result, the pharmaceutical composition described herein is suitable for oral administration and can improve absorption in the gastrointestinal tract, thereby improving bioavailability, compared to remdesivir alone and in the presence of SBE β CD. Furthermore, remdesivir in the pharmaceutical compositions described herein can also be readily diluted in aqueous media without risk of precipitation, thereby allowing the use of the solubilizing excipient SBE, which is contraindicated as an injection, infusion, or in infants and adults with impaired renal function. It provides a drug dosing strategy as an oral solution of various concentrations that allows precise dosing without requiring large amounts of β CD.

Beagle in vivo study

A dog in vivo study in beagles was conducted according to 1) a single intravenous (IV) infusion of a control formulation and 2) an oral (PO) dose of the exemplary pharmaceutical composition ES040-72 according to the present invention to evaluate the pharmacokinetics of remdesivir ( PK) profile was determined.

Pharmaceutical Composition Used in Beagle Study - ES040-72 ingredient weight (g) %(w/w) Remdesivir 2.02 6.7 Polyethylene glycol 400 (PEG 400) 15.7721 52.34 Polyethylene glycol 300 (PEG 300) 4.7435 15.74 Cysteine Hydrochloride Monohydrate, USP 4.7370 5.76 N-acetyl-L-cysteine 1.7744 5.89 Twin 80-NV-LQ-(AP) 1.7227 5.72 Ethyl Alcohol, 190 Proof, USP 1.0244 3.40 Benzyl Alcohol, BP, NF, Ph.Eur 1.3371 4.44 gross weight 30.1312

Test systems for in vivo studies strain/species/sex Dog (Canis familiaris) / Beagle / Male source test facility stock colonies; Originally obtained from Marshall BioResources, Northrose, NY, USA check Tattoos matching cage cards number of animals 3 males age range Between 10 months and 3 years weight range approximately 9 to 11 kg Record Animals were not experimentally pure Housing/Sanitary Confinement of animals individually in cages appropriate to the species diet Certified dog food is provided daily in amounts appropriate to the animal's size and age. water Can drink tap water voluntarily fast Animals were fasted overnight, followed by 4 hour sample collection, and daily doses were given 4 hours after dosing. environment Temperature: 64 to 84°F (18 to 29°C)
Humidity: 30 to 70%
Light: Maintain alternating 12-hour light/dark cycles, except during certain study procedures
Ventilation: Airflow set to be ventilated at least 10 times per hour, 100% fresh air (no air recirculation)

Dosage of control and example formulations test product number of dogs (males) route of administration capacity level
(mg/kg) dose concentration
(mg/mL) capacity volume
(mL/kg) Control ^a 3 IV ^a 20 ^2a 10 Example pharmaceutical composition ES040-72 ^b 3 Oral (PO) ^b 20 about 50 to 60 ^b from about 0.4 to 0.333 ^b

a - The remdesivir control formulation (5 mg/mL solution) was matched to VEKLURY ^® (ie, a commercially available remdesivir formulation). It was diluted to 2 mg/mL with sterile water for injection (WFI). Appropriate doses (by weight) were administered by single 30-minute infusions via the radial vein using a Medfusion 2001 syringe pump.

b - Example Pharmaceutical composition ES040-72 was placed in Torpac hard gelatin capsule size #12 (ie, 5 mL volume) for dosing. The appropriate dose volume was calculated based on the correct dose concentration. Dogs received a single Torpak capsule. After administration of the capsule, a squirt of water was given orally to assist in the delivery of the capsule to the stomach.

plasma collection

For doses administered IV or orally (PO), plasma samples were collected over a period of 48 hours. Additional details of plasma collection are detailed in Table 13.

Blood sample collection for plasma sampling location Jugular vein or alternative non-administered vein blood sample volume about 1 mL Plasma time point All analytes were stabilized by adding a protease inhibitor cocktail (see manufacturing instructions outlined in footnote) equal to 5% of the blood volume (i.e., 50 μl added to 1 mL of blood) to the blood collection tube.
From each animal in Group IV, before dosing, at 5 minutes (during infusion), 15 minutes (during infusion), 30 minutes (end of infusion), 35 minutes, 45 minutes, 1 hour, 2 hours, 12 hours from start of infusion, Blood was collected at 24 hours and 48 hours. The time point is relative to the start of the infusion.
Blood was collected from each animal in the PO group before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after infusion. full blood condition After collection, samples were inverted several times and kept on ice until centrifugation. anticoagulant K3EDTA Separation method Samples were centrifuged under refrigeration within 30 minutes of collection (set at 2000 g for 10 minutes at 5°C). Plasma samples were stored in a freezer set to remain below -70°C until analysis. bioanalysis LC-MS/MS analysis of plasma samples was performed using a Frontage Tier 2 non-GLP bioanalysis. Plasma was assayed for (GS-441524), Compound C. Pharmacokinetic analysis Concentrations of the analytes determined by the LC/MS/MS method were used to determine pharmacokinetic parameters by Phoenix ^® WinNonlin ^® software (version 8.1, Certara, Princeton, NJ, USA) using non-compartmental analysis. .

Protease Cocktail Instructions: a. Add 1 mL of KF solution (4 mg/mL) [prepared by weighing 80 mg of KF and mixing with 20 mL of ultrapure deionized water], b. Dissolve 1 complete tablet (Easypack protease inhibitor cocktail tablets without mini EDTA, Roche, catalog number 04 693 159 001), c. Mix thoroughly until tablet is dissolved, d. Add 1 mL of a 25 mM EDTA solution in water (adjust pH to 7 with 1 N potassium hydroxide), e. mix thoroughly, f. Store at 2-8°C.

Collection of peripheral blood mononuclear cells (PBMCs)

For both doses administered IV or orally (PO), blood samples were collected to determine the presence of analytes in PBMCs. Additional details are detailed in Table 14.

PBMC collection sampling location Jugular vein or alternative non-administered vein blood sample volume about 4 mL sample collection All analytes were stabilized by adding a protease inhibitor cocktail (see manufacturing instructions outlined in footnote) equal to 5% of the blood volume (i.e., 200 μL added to 4 mL of blood) to the blood collection tube. Blood was collected into cell prep tubes at multiple time points after dosing. full blood condition Cell prep tubes were stored on ice after blood collection and processed within 2 hours of collection. The tube was inverted several times before centrifugation. anticoagulant sodium citrate Separation method 1. Centrifuge the CPT tube in a horizontal rotor (swing out head) set at 18°C, 30 min, 1700 Х g.
2. After centrifugation, invert gently 5 to 10 times without opening the tube to resuspend the cells in the plasma. Open the tube cap to collect the cells and transfer the entire contents of the tube above the gel to a separate 15 mL conical tube using a disposable transfer pipette.
3. Add PBS (Phosphate Buffered Saline) to bring the volume to the 15 mL grid in the conical tube and mix by inversion 5 times. Set the centrifuge tube to 18°C, 15 minutes, 300 Х g.
4. Using a disposable transfer pipette, aspirate and discard as much of the supernatant as possible without disturbing the cell pellet.
5. Resuspend the cell pellet by gently vortexing.
6. Using a graduated disposable pipette, add 10 mL PBS to the tube and invert 5 times to mix the cells. Centrifugation is set at 18°C, 10 min, 300 Х g.
7. Using a disposable transfer pipette, aspirate and discard as much of the supernatant as possible without disturbing the cell pellet.
8. Bake the cell pellets in liquid nitrogen in the same tube and store in a freezer set to keep below -70°C. bioanalysis LC-MS/MS analysis of plasma samples was performed using a Frontage Tier 2 non-GLP bioanalysis. Plasma was assayed for (GS-441524), Compound C.

result

As shown in Figure 3 and demonstrated by Table 15, the oral dosage form successfully matches systemic exposure of the major active metabolite GS-441524 by both IV and oral routes of administration. In plasma after IV administration, this same major metabolite is detected at levels that are sustained well beyond the levels of the prodrug remdesivir as reported in primate and human studies, suggesting that GS-441524 is absorbed into target tissues and There is evidence to suggest that it is converted to an active triphosphate metabolite after phosphorylation. GS-441524 has already been shown in the literature to exhibit significant in vitro activity against a variety of SARS-CoV-2 infected cell lines, and plasma concentrations of this metabolite consistently exceed its EC50 after IV administration in vivo; The concentration of remdesivir decreases quickly enough below its EC50. As a result, following oral administration of remdesivir, matching exposure and plasma levels of key metabolites are expected to demonstrate comparable pharmacological activity as IV infusion.

Nonetheless, the pharmaceutical formulation of the present invention and the strategy of administering remdesivir in place of GS-441524 are important to achieve maximal concentration and exposure of GS-441524. GS-441524 alone has poor oral bioavailability due to poor permeability through the intestinal membrane.

Summary of Plasma Pharmacokinetics for GS-441524, Compound C administration nominal capacity AUC _Final (h*ng/mL) AUC _inf (h*ng/mL) t _1/2 (h) t _max (h) _Cmax (ng/mL) IV 20 mg/kg 19800±2510 22000±1950 15.6±2.92 1.67±0.577 1240±203 Oral (PO) 20 mg/kg 21500±2100 21700±2170 6.81±0.270 1.33±0.577 1980±270

Additionally, GS-441524 (Compound C) was detected in PBMC cells after IV and oral (PO) administration.

Metabolic studies in vitro

The relative abundance (%) of metabolites after incubation with remdesivir (10 μM) was determined after cultivation with human hepatocytes (1.3 million cells/mL). The results are shown in Table 16.

Electrospray ionization with in-line UV detection with a photodiode array detector is used to obtain high-resolution, accurate mass data, followed by ultra-performance liquid chromatography with a quadrupole time-of-flight mass spectrometer. Samples were analyzed by graphical tandem mass spectrometry (UHPLC-MS/MS).

Relative abundance of analyte after incubation with remdesivir ingredient 2 hours 6 hours 24 hours Remdesivir Compound (A) 4.8 0.1 0.7 GS-704277 (alanine metabolite) compound (B) 0.0 2.4 2.2 Nucleoside monophosphate (RT 1.32 min) ND 24.8 13.4 Nucleoside monophosphate (RT 2.15 min) 44.6 7.5 3.6 GS-441524 Compound C 50.6 65.1 80.1 cyclic anhydrides ND ND ND nucleoside triphosphate ND ND ND

ND- not detected

These results predict that the major end product of first pass metabolism of remdesivir by the liver is GS-441524, the same metabolite as the major and retained species in plasma following intravenous (IV) administration of remdesivir. prove that After IV administration, remdesivir is converted to GS-441524 by esterases present in the blood. Accordingly, these in vitro results suggest that exposure to GS-441524 is the same as after IV administration.

Claims (17)

A compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient selected from cysteine compounds, amino acids, amino acid salts, N -acetyl amino acids, acids or salts thereof, or any combination thereof. A pharmaceutical composition comprising:
[Formula I]

wherein X is hydroxyl, metal salt hydroxylate, O-linked phosphoester, O-linked phosphoramidite, O-linked ester, O-linked carbamate, S-linked phosphothioate, or selected from N-linked phosphoramidites). The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is free of cyclodextrin. 3. The pharmaceutical composition according to claim 1 or 2, wherein the at least one pharmaceutically acceptable excipient comprises at least one cysteine compound. 4. The pharmaceutical composition according to any one of claims 3 to 3, wherein the at least one cysteine compound is cysteine hydrochloride and/or N -acetyl cysteine. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is a liquid dosage form, and the pharmaceutical composition comprises one or more co-solvents. 6. The pharmaceutical composition according to claim 5, wherein the one or more cosolvents are selected from PEG, benzyl alcohol, ethanol or combinations thereof. According to claim 5 or 6,
3 to 10% w/w of a compound of formula I;
0.5 to 30% w/w of a cysteine compound,
50 to 86% w/w of one or more co-solvents
A pharmaceutical composition comprising a. 8. The pharmaceutical composition according to any one of claims 1 to 7, comprising one or more surfactants. 9. The pharmaceutical composition of claim 8, wherein the at least one surfactant comprises polysorbate. According to claim 8 or 10,
3 to 10% w/w of a compound of formula I
1-15% w/w cysteine hydrochloride monohydrate
3-15% w/w N -acetyl cysteine
50 to 83% w/w of one or more co-solvents
2 to 8% w/w surfactant
A pharmaceutical composition comprising a. 11. The compound of formula I according to any one of claims 1 to 10

Phosphorus pharmaceutical composition. A method of treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 11. 12. The method of claim 11, wherein the virus causing the viral infection is coronavirus, respiratory syncytial virus, ebola, hepatitis, junin, lassa fever, orthomyxovirus, hepatitis virus (HV) type, disease- Causes picornaviruses, Ebola, SARS, MERS, respiratory syncytial virus and other pneumococcal viruses, influenza, poliomyelitis and adult human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) A method selected from retroviruses comprising 14. The method of claim 12 or 13, wherein the pharmaceutical composition is administered orally or parenterally. A capsule comprising the pharmaceutical composition of any one of claims 1 to 11. An oral solution comprising the pharmaceutical composition of any one of claims 1 to 11. An injectable solution comprising the pharmaceutical composition of any one of claims 1 to 11.

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